Antibody molecules to a proliferation-inducing ligand (april)

ABSTRACT

Antibody molecules that specifically bind to APRIL are disclosed. The antibody molecules can be used to treat, prevent, and/or diagnose disorders, such as IgA nephropathy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 16/456,810, filed Jun. 28, 2019, which is a divisionalapplication of U.S. patent application Ser. No. 16/212,957 filed Dec. 7,2018, now U.S. Pat. No. 10,385,123, which is a divisional application ofU.S. patent application Ser. No. 15/360,145, filed Nov. 23, 2016, nowabandoned, which claims the benefit of U.S. Provisional Application No.62/259,897, filed Nov. 25, 2015, U.S. Provisional Application No.62/313,684, filed Mar. 25, 2016, U.S. Provisional Application No.62/399,087, filed Sep. 23, 2016, and U.S. Provisional Application No.62/422,848, filed Nov. 16, 2016. The contents of the aforementionedapplications are hereby incorporated by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Nov. 21, 2016, isnamed P2029-700410_SL.txt and is 248,428 bytes in size.

BACKGROUND

IgA nephropathy is one of the most prevalent, chronic glomerulardiseases worldwide. Conservative epidemiological estimates cite a globalincidence of approximately 5-50 cases/million (children) and 10-40cases/million (adults). This incidence of disease presents a regionalbias with a higher prevalence in Asia and the Americas, with aparticularly higher disease burden in Japan and regions of China. Biopsyconfirmed cases of IgA nephropathy in Japan are projected atapproximately 350,000. In the US, this projection is approximately100,000—as such, it is the most frequently diagnosed 1° glomerulardisease in adults. While a relatively indolent disease, IgA nephropathyleads to end stage renal disease (ESRD), i.e., renal failure in 20-50%of patients within a 20-30 year span. These numbers are likely grosslyunderreported given the need to confirm the disease by kidney biopsy, aprotocol that is variably practiced in various clinical settings. Thedisease has a complex pathogenesis with genetic, epidemiological, andpotentially environmental components to disease etiology, pathology, andprogression. It likewise has a variable clinical presentation rangingfrom asymptomatic to end-stage renal failure (ESRD). IgA nephropathy iscaused by the deposition of IgA, typically in the form of immunecomplexes in the mesangium of the kidney. There are currently nodisease-specific treatments to address primary disease or progression.

There is a need for developing new approaches for treating, preventingand diagnosing IgA nephropathy and other disorders that share similardisease mechanisms.

SUMMARY

This disclosure provides, at least in part, antibody molecules that bindto APRIL, e.g., human and/or mouse APRIL, and that comprise one or morefunctional and structural properties disclosed herein. In an embodiment,the antibody molecule binds to and/or reduces (e.g., inhibits, blocks orneutralizes) one or more activities of APRIL. In an embodiment, theantibody molecule binds to a region in APRIL that interacts with TACI(e.g., the CRD2 domain of TACI). In an embodiment, the antibody moleculebinds to one or more residues within a region of human APRIL as definedin any of Tables 3-4 or 7-8. While not wishing to be bound by theory, itis believed that in an embodiment, improved or optimal inhibition ofAPRIL activities can be achieved, by targeting certain region(s) onAPRIL (e.g., the region(s) associated with the interactions betweenAPRIL and the CDR2 domain of TACI). In an embodiment, the antibodymolecule is selected from Table 1 or 5, or competes for binding to APRILwith an antibody molecule selected from Table 1 or 5. In an embodiment,the antibody molecule binds to the same or overlapping epitope as theepitope recognized by an antibody molecule selected from Table 1 or 5.In an embodiment, the antibody molecule comprises one or more heavychain variable regions and/or one or more light chain variable regionsdescribed in Table 1 or 5. In an embodiment, the antibody moleculecomprises one or more heavy chain CDRs and/or one or more light chainCDRs described in Table 1 or 5. In an embodiment, nucleic acid moleculesencoding the antibody molecules, expression vectors, host cells,compositions (e.g., pharmaceutical compositions), kits, containers, andmethods for making the antibody molecules, are also provided. Theantibody molecules disclosed herein can be used (alone or in combinationwith other agents or therapeutic modalities) to treat, prevent and/ordiagnose disorders associated with APRIL, such as IgA nephropathy.

Accordingly, in certain aspects, this disclosure provides an antibodymolecule, e.g., an antibody molecule described herein, having one ormore (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, or 23) of the following properties:

-   -   a) Binds to human APRIL with high affinity, e.g., with a        dissociation constant (K_(D)) of less than about 100 nM,        typically about 10 nM, and more typically, about 10-0.001 nM,        about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1        nM, or stronger, e.g., less than about 80, 70, 60, 50, 40, 30,        20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or        0.001 nM,    -   b) Binds to mouse APRIL with high affinity, e.g., with a        dissociation constant (K_(D)) of less than about 100 nM,        typically about 10 nM, and more typically, about 10-0.001 nM,        about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1        nM, or stronger, e.g., less than about 80, 70, 60, 50, 40, 30,        20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or        0.001 nM,    -   c) Does not bind to mouse APRIL, or binds mouse APRIL with low        affinity, e.g., with a dissociation constant (K_(D)) of greater        than about 500 nM, e.g., greater than about 1000 nM,    -   d) Does not bind, or binds with low affinity, e.g., with a        dissociation constant (K_(D)) of greater than about 500 nM,        e.g., greater than about 1000 nM, to one or more (e.g., 2, 3, 4,        5, 6, 7, 8, or more) cytokines from the TNF superfamily (TNFSF)        other than APRIL (e.g., TNFα, CD40 (TNFSF4), FasL (TNFSF6),        TRAIL (TNFSF10), RANKL (TNFSF11), Tweak (TNFSF12), BAFF        (TNFSF13B), or LIGHT (TNFSF14)),    -   e) Binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all)        residues within a region of APRIL as defined in Table 3, or        binds specifically to an epitope on APRIL, e.g., an epitope        comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all)        residues described in Table 3,    -   f) Binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or        all) residues within a region of APRIL as defined in Table 4, or        binds specifically to an epitope on APRIL, e.g., an epitope        comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or        all) residues described in Table 4,    -   g) Binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, 14, 15, 16, 17, or all) residues within a region of        APRIL as defined in Table 7, or binds specifically to an epitope        on APRIL, e.g., an epitope comprising one or more (e.g., 2, 3,        4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all)        residues described in Table 7,    -   h) Binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all)        residues within a region of APRIL as defined in Table 8, or        binds specifically to an epitope on APRIL, e.g., an epitope        comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,        12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all)        residues described in Table 8,    -   i) Binds specifically to an epitope on APRIL, e.g., the same,        similar, or overlapping epitope as the epitope recognized by a        monoclonal antibody described in Table 1 or 5, e.g., any of        monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205,        2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,        2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,        2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035,        4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063,        4540-033, 4439, or 4237,    -   j) Reduces (e.g., inhibits, blocks, or neutralizes) one or more        biological activities of APRIL (e.g., human APRIL, mouse APRIL,        or both), in vitro, ex vivo, or in vivo,    -   k) Reduces (e.g., inhibits, blocks, or neutralizes) binding of        human APRIL to TACI, e.g., at an IC₅₀ of about 50 nM or less,        typically about 0.01-50 nM, 0.1-25 nM, 0.1-10 nM, 0.5-5 nM, or        1-5 nM, e.g., less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2,        0.1, 0.05, or 0.01 nM, e.g., as determined by a method described        herein,    -   1) Reduces (e.g., inhibits, blocks, or neutralizes) binding of        mouse APRIL to TACI, e.g., at an IC₅₀ of about 100 nM or less,        typically about 0.01-75 nM, 0.1-50 nM, 0.1-25 nM, 0.1-10 nM,        0.5-5 nM, or 1-5 nM, e.g., less than about 80, 60, 40, 20, 10,        5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01 nM, e.g., as determined by a        method described herein,    -   m) Reduces (e.g., inhibits, blocks, or neutralizes) binding of        human APRIL to BMCA, e.g., at an IC₅₀ of about 50 nM or less,        typically about 0.01-50 nM, 0.1-25 nM, 0.1-10 nM, 0.5-5 nM, or        1-5 nM, e.g., less than about 40, 30, 20, 10, 5, 1, 0.5, 0.2,        0.1, 0.05, or 0.01 nM, e.g., as determined by a method described        herein,    -   n) Reduces (e.g., inhibits, blocks, or neutralizes) binding of        mouse APRIL to BMCA, e.g., at an IC₅₀ of about 200 nM or less,        typically about 0.01-200 nM, 0.1-150 nM, 0.1-100 nM, 0.1-50 nM,        0.1-25 nM, 0.1-10 nM, 0.5-5 nM, or 1-5 nM, e.g., less than about        150, 100, 50, 40, 30, 20, 10, 5, 1, 0.5, 0.2, 0.1, 0.05, or 0.01        nM, e.g., as determined by a method described herein,    -   o) Shows the same or similar binding affinity or specificity, or        both, as a monoclonal antibody described in Table 1 or 5, e.g.,        any of monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205,        2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,        2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,        2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035,        4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063,        4540-033, 4439, or 4237,    -   p) Shows the same or similar binding affinity or specificity, or        both, as an antibody molecule comprising a heavy chain variable        region and/or light chain variable region described in Table 1        or 5, e.g., a heavy chain variable region and/or light chain        variable region of any of monoclonal antibodies 2218, 2419,        2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605,        2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210,        2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530,        3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338,        4540, 4540-063, 4540-033, 4439, or 4237,    -   q) Shows the same or similar binding affinity or specificity, or        both, as an antibody molecule comprising one or more (e.g., two        or three) heavy chain CDRs and/or one or more (e.g., two or        three) light chain CDRs described in Table 1 or 5, e.g., one or        more (e.g., two or three) heavy chain CDRs and/or one or more        (two or three) light chain CDRs of any of monoclonal antibodies        2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,        2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205,        2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922,        3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631,        3732, 4338, 4540, 4540-063, 4540-033, 4439, or 4237,    -   r) Shows the same or similar binding affinity or specificity, or        both, as an antibody molecule comprising an amino acid sequence        shown in Table 1 or 5,    -   s) Shows the same or similar binding affinity or specificity, or        both, as an antibody molecule comprising an amino acid sequence        encoded by a nucleotide sequence shown in Table 2,    -   t) Inhibits, e.g., competitively inhibits, the binding of a        second antibody molecule to human APRIL, mouse APRIL, or both,        wherein the second antibody molecule is an antibody molecule        chosen from Table 1 or 5, e.g., any of monoclonal antibodies        2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,        2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205,        2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922,        3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631,        3732, 4338, 4540, 4540-063, 4540-033, 4439, or 4237,    -   u) Competes for binding with a second antibody molecule to human        APRIL, mouse APRIL, or both, wherein the second antibody        molecule is a monoclonal antibody chosen from Table 1 or 5,        e.g., any of monoclonal antibodies 2218, 2419, 2419-0105,        2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,        2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305,        2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125,        2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540,        4540-063, 4540-033, 4439, or 4237,    -   v) Has one or more biological properties of a monoclonal        antibody chosen from Table 1 or 5, e.g., any of monoclonal        antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206,        2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,        2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,        2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062,        3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or        4237,    -   w) Has one or more structural properties of a monoclonal        antibody chosen from Table 1 or 5, e.g., any of monoclonal        antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206,        2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,        2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,        2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062,        3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or        4237, or    -   x) Has one or more pharmacokinetic properties of a monoclonal        antibody chosen from Table 1 or 5, e.g., any of monoclonal        antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206,        2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,        2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,        2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062,        3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or        4237.

In an aspect, the disclosure features an anti-APRIL antibody molecule,which:

(i) binds, or substantially binds, to human APRIL;

(ii) binds, or substantially binds, to mouse APRIL;

(iii) inhibits, or substantially inhibits, binding of APRIL (e.g., humanAPRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, orboth); and

(iv) inhibits, or substantially inhibits, binding of APRIL (e.g., humanAPRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, orboth).

In an embodiment, the antibody molecule is a synthetic antibodymolecule. In an embodiment, the antibody molecule is an isolatedantibody molecule.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), e.g., at an IC₅₀ of 200 nMor less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less,30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less,7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM orless, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less,0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nMand 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein. In an embodiment, the antibody molecule is anIgG antibody molecule, e.g., comprising a heavy chain constant region ofIgG, e.g., chosen from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g.,IgG2 or IgG4. In an embodiment, the antibody molecule is an IgG1antibody molecule, e.g., having an IgG1 constant region describedherein. In another embodiment, the antibody molecule is an IgG2 antibodymolecule e.g., having an IgG2 constant region described herein. In anembodiment, the antibody molecule comprises a light chain constantregion of kappa or lambda light chain.

In an embodiment, the antibody molecule comprises an Fc region. In anembodiment, the Fc region comprises one or more mutations located at theinterface between the CH2 and CH3 domains (e.g., to increase the bindingaffinity to neonatal receptor FcRn and/or the half-life of the antibodymolecule). In an embodiment, the Fc region comprises one or moremutations, e.g., one or more (e.g., 2, 3, 4, 5, 6 or all) mutationschosen from T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or anycombination thereof, of IgG1. In an embodiment, the Fc region comprisesone or more mutations at positions 233-236 or 322 of human IgG1 or IgG2,or one or more substitutions at positions 327, 330 or 331 of human IgG4(e.g., to reduce complement-dependent cytotoxicity (CDC)). In anembodiment, the Fc region comprises one or more (e.g., 2, 3, 4, 5, 6, 7or all) mutations chosen from E233P, L234V, L235A, G236, K322A, A327G,A330S, P331S, or any combination thereof.

In an embodiment, the antibody molecule is a humanized antibodymolecule, e.g., comprising one or more framework regions derived fromhuman framework germline sequence. In an embodiment, the antibodymolecule comprises a heavy chain variable region (VH) described in Table1 or 5. In an embodiment, the antibody molecule comprises a light chainvariable region (VL) described in Table 1 or 5. In an embodiment, theantibody molecule comprises a heavy chain variable region (VH) and alight chain variable region (VL) described in Table 1 or 5. In anembodiment, the antibody molecule comprises one, two, or three CDRs of aheavy chain variable region (VH) described in Table 1 or 5. In anembodiment, the antibody molecule comprises one, two, or three CDRs of alight chain variable region (VL) described in Table 1 or 5. In anembodiment, the antibody molecule comprises one, two, or three CDRs of aheavy chain variable region (VH) described in Table 1 or 5, and one,two, or three CDRs of a light chain variable region (VL) described inTable 1 or 5. In an embodiment, the antibody molecule comprises twoheavy chain variable regions and two light chain variable regions. In anembodiment, the antibody molecule is a Fab, F(ab′)2, Fv, Fd, or a singlechain Fv fragment (scFv).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 61); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 62); or (ii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 61); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:62); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 61); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 62);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 64); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 64); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:65); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 64); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 65);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3530 (e.g., SEQ ID NO: 70). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 66); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3530 (e.g., SEQID NO: 70).

In an embodiment the antibody molecule is monoclonal antibody 3530. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3530.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 62); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 61); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:62); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody3525 (e.g., SEQ ID NO: 61); an HCDR2 comprising the amino acid sequenceof the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62); and anHCDR3 comprising the amino acid sequence of the HCDR3 of monoclonalantibody 3525 (e.g., SEQ ID NO: 63), and (ii) a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising the amino acid sequenceof the LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); and anLCDR3 comprising the amino acid sequence of the LCDR3 of monoclonalantibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 64); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 64); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:65); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprises the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 64); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 65);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3525 (e.g., SEQ ID NO: 50). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 66); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3525 (e.g., SEQID NO: 50).

In an embodiment the antibody molecule is monoclonal antibody 3525. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3525.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 113); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 114); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 115).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 118).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 113); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:114); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:117); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody3833 (e.g., SEQ ID NO: 113); an HCDR2 comprising the amino acid sequenceof the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114); and anHCDR3 comprising the amino acid sequence of the HCDR3 of monoclonalantibody 3833 (e.g., SEQ ID NO: 115), and (ii) a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising the amino acid sequenceof the LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); and anLCDR3 comprising the amino acid sequence of the LCDR3 of monoclonalantibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 119); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 120); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 115).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 118).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 119); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:120); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:117); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprises the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 119); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:120); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQID NO: 117); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3833 (e.g., SEQ ID NO: 122). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 121); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3833(e.g., SEQ ID NO: 122).

In an embodiment the antibody molecule is monoclonal antibody 3833. Inan embodiment, monoclonal antibody 3833 is a humanized monoclonalantibody 3833. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 246-250, a VLcomprising the amino acid sequence of any of SEQ ID NO: 251-253, orboth.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 124); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 125).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 128).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 123); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:124); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody3631 (e.g., SEQ ID NO: 123); an HCDR2 comprising the amino acid sequenceof the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 124); and anHCDR3 comprising the amino acid sequence of the HCDR3 of monoclonalantibody 3631 (e.g., SEQ ID NO: 125), and (ii) a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising the amino acid sequenceof the LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); and anLCDR3 comprising the amino acid sequence of the LCDR3 of monoclonalantibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: an HCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129); an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 130); or an HCDR3 comprising an aminoacid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 125).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: an LCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 127); or an LCDR3 comprising an aminoacid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 128).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 129); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:130); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprises the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 129); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:130); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3631 (e.g., SEQ ID NO: 132). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 131); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3631(e.g., SEQ ID NO: 132).

In an embodiment the antibody molecule is monoclonal antibody 3631. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3631.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 134); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 135).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 137).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 133); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:134); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody3732 (e.g., SEQ ID NO: 133); an HCDR2 comprising the amino acid sequenceof the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134); and anHCDR3 comprising the amino acid sequence of the HCDR3 of monoclonalantibody 3732 (e.g., SEQ ID NO: 135), and (ii) a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising the amino acid sequenceof the LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); and anLCDR3 comprising the amino acid sequence of the LCDR3 of monoclonalantibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 138); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 139); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 135).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 137).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 138); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:139); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprises the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 138); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:139); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3732 (e.g., SEQ ID NO: 141). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 140); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3732(e.g., SEQ ID NO: 141).

In an embodiment the antibody molecule is monoclonal antibody 3732. Inan embodiment, monoclonal antibody 3732 is a humanized monoclonalantibody 3732.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g.,SEQ ID NO: 154); (ii) an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQID NO: 155); or (iii) an HCDR3 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQID NO: 156).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116),4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ IDNO: 275), or 4540-033 (e.g., SEQ ID NO: 275); or (iii) an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 154); an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 155); or an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274),or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 154); an HCDR2 comprisingthe amino acid sequence of the HCDR2 of monoclonal antibody 4540,4540-063, or 4540-033 (e.g., SEQ ID NO: 155); and an HCDR3 comprisingthe amino acid sequence of the HCDR3 of monoclonal antibody 4540,4540-063, or 4540-033 (e.g., SEQ ID NO: 156), and (ii) a light chainvariable region (VL), wherein the light chain variable region comprisesthree light chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274), or4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising the amino acidsequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); and an LCDR3 comprising the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 159),4540-063 (e.g., SEQ ID NO: 276), or 4540-033 (e.g., SEQ ID NO: 159);(ii) an HCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (e.g., SEQ IDNO: 277), or 4540-033 (e.g., SEQ ID NO: 278); or (iii) an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116),4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ IDNO: 275), or 4540-033 (e.g., SEQ ID NO: 275); or (iii) an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 159), 4540-063 (e.g., SEQ ID NO: 276),or 4540-033 (e.g., SEQ ID NO: 159); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:160), 4540-063 (e.g., SEQ ID NO: 277), or 4540-033 (e.g., SEQ ID NO:278); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156),and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274),or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingone, two, or all of the following: an HCDR1 comprising the amino acidsequence of the HCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO:159), 4540-063 (e.g., SEQ ID NO: 276), or 4540-033 (e.g., SEQ ID NO:159); an HCDR2 comprising the amino acid sequence of the HCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (e.g., SEQ IDNO: 277), or 4540-033 (e.g., SEQ ID NO: 278); or an HCDR3 comprising theamino acid sequence of the HCDR3 of monoclonal antibody 4540, 4540-063,or 4540-033 (e.g., SEQ ID NO: 156), and (ii) a VL comprising one, two,or all of the following: an LCDR1 comprising the amino acid sequence ofthe LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116), 4540-063(e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2comprising the amino acid sequence of the LCDR2 of monoclonal antibody4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ ID NO: 275), or4540-033 (e.g., SEQ ID NO: 275); or an LCDR3 comprising the amino acidsequence of the LCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033(e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4540 (e.g., SEQ ID NO: 161),4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063(e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4540 (e.g., SEQ ID NO: 161),4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256); and(ii) a VL comprising an amino acid sequence that differs by no more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residuesfrom, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with,the amino acid sequence of the VL of monoclonal antibody 4540 (e.g., SEQID NO: 162), 4540-063 (e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ IDNO: 261). In an embodiment, the antibody molecule comprises: (i) a VHcomprising the amino acid sequence of the VH of monoclonal antibody 4540(e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258), or 4540-033(e.g., SEQ ID NO: 256); and (ii) a VL comprising the amino acid sequenceof the VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063(e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261).

In an embodiment, the antibody molecule is monoclonal antibody 4540,4540-063, or 4540-033. In an embodiment, monoclonal antibody 4540 is ahumanized monoclonal antibody 4540 (e.g., antibodies 4540-063 or4540-033). In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 254-258, a VLcomprising the amino acid sequence of any of SEQ ID NO: 259-261, orboth.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in any of Tables 3-4 or 7-8.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in Table 3. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatcomprises or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, ofthe human APRIL residues from Table 3. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 3. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises APRIL residues fromtwo monomers, e.g., one or more residues from monomer A and monomer B asshown in Table 3.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, residueswithin a region of human APRIL as defined in Table 4. In an embodiment,the antibody molecule binds, or substantially binds, to an epitope thatcomprises or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,or all, of the human APRIL residues from Table 4. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatoverlaps an epitope that comprises or consists of all of the human APRILresidues from Table 4. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises one or more APRILresidues from the C-D loop (e.g., the loop connecting β-sheets C and D),the G-H loop (e.g., the loop connecting β-sheets G and H), or both.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or all, residues within a region of human APRIL as defined inTable 7. In an embodiment, the antibody molecule binds, or substantiallybinds, to an epitope that comprises or consists of one or more, e.g., 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all, of thehuman APRIL residues from Table 7. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 7.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, residues within a regionof human APRIL as defined in Table 8. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that comprises orconsists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, of the humanAPRIL residues from Table 8. In an embodiment, the antibody moleculebinds, or substantially binds, to an epitope that overlaps an epitopethat comprises or consists of all of the human APRIL residues from Table8.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of humanAPRIL from positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7,8, 9, or all) residues of mouse APRIL from positions 96-105. In anembodiment, the antibody molecule does not bind, or does notsubstantially bind, to one, two or all of Asp129, Arg233, or His203 ofhuman APRIL. In an embodiment, the epitope is a conformational epitope.

In an embodiment, binding of the antibody molecule to APRIL (e.g., humanAPRIL) inhibits, or substantially inhibits, the binding of the CRD2domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL). Inanother embodiment, binding of the antibody molecule to human APRIL,inhibits, or substantially inhibits, the binding of human TACI, to oneor more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, or all, of the APRIL residues from Table3. In yet another embodiment, binding of the antibody molecule to humanAPRIL, inhibits, or substantially inhibits, the binding of human TACI,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all, of the humanAPRIL residues from Table 4. In still another embodiment, binding of theantibody molecule to human APRIL, inhibits, or substantially inhibits,the binding of human TACI, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, or all, of the human APRIL residues fromTable 7. In still another embodiment, binding of the antibody moleculeto human APRIL, inhibits, or substantially inhibits, the binding ofhuman TACI, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, of the humanAPRIL residues from Table 8. In another embodiment, binding of theantibody molecule to human APRIL inhibits, or substantially inhibits,the binding of human BCMA, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all,of the human APRIL residues from Table 8.

In an aspect, the disclosure features an antibody molecule that binds,or substantially binds, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more,residues within a region of human APRIL as defined in any of Tables 3-4or 7-8. In an embodiment, the anti-APRIL antibody molecule binds, orsubstantially binds, to an epitope that comprises or consists of one ormore, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, or more, of the human APRIL residues fromany of Tables 3-4 or 7-8. In an embodiment, the antibody molecule binds,or substantially binds, to a conformational epitope.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in Table 3. In an embodiment, theanti-APRIL antibody molecule binds, or substantially binds, to anepitope that comprises or consists of one or more (e.g., 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,or all) of the human APRIL residues from Table 3. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatcomprises APRIL residues from two monomers, e.g., one or more residuesfrom monomer A and monomer B as shown in Table 3.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all, residueswithin a region of human APRIL as defined in Table 4. In an embodiment,the epitope comprises consists of one or more, e.g., 2, 3, 4, 5, 6, 7,8, 9, 10, or all of the APRIL residues from Table 4. In an embodiment,the epitope comprises or consists of one or more APRIL residues from theC-D loop (e.g., the loop connecting β-sheets C and D), the G-H loop(e.g., the loop connecting β-sheets G and H), or both.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or all, residues within a region of human APRIL as defined inTable 7. In an embodiment, the antibody molecule binds, or substantiallybinds, to an epitope that comprises or consists of one or more, e.g., 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all, of thehuman APRIL residues from Table 7. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 7.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, residues within a regionof human APRIL as defined in Table 8. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that comprises orconsists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, of the humanAPRIL residues from Table 8. In an embodiment, the antibody moleculebinds, or substantially binds, to an epitope that overlaps an epitopethat comprises or consists of all of the human APRIL residues from Table8.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of humanAPRIL from positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7,8, 9, or all) residues of mouse APRIL from positions 96-105. In anembodiment, the antibody molecule does not bind, or does notsubstantially bind, to one, two or all of Asp129, Arg233, or His203 ofhuman APRIL.

In an embodiment, the antibody molecule binds, or substantially binds,to an epitope that comprises or consists of one or more (e.g., 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, or all) of human APRIL residues fromTable 6.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more (e.g., 2, 3, 4, 5, or all) of the amino acid residues ofhuman APRIL chosen from V174, F176, Q190, R195, R206, or Y208. In anembodiment, the antibody molecule does not binds, or does notsubstantially bind, to one or more (e.g., 2, 3, or all) of the aminoacid residues of human APRIL chosen from V181, S226, 1228, or N237. Inan embodiment, the antibody molecule binds, or substantially binds, toone or more (e.g., 2, 3, or all) of the amino acid residues of humanAPRIL chosen from F176, V181, Q190, or 1228. In an embodiment, theantibody molecule does not bind, or does not substantially bind, to oneor both of the amino acid residues of human APRIL chosen from Y208 orN237. In an embodiment, the antibody molecule binds, or substantiallybinds, to one or more (e.g., 2, or all) of the amino acid residues ofhuman APRIL chosen from V174, R206, or Y208. In an embodiment, theantibody molecule does not bind, or does not substantially bind, to oneor more (e.g., 2, 3, or all) of the amino acid residues of human APRILchosen from F176, V181, Q190, or N237.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL and mouse APRIL. In an embodiment,the antibody molecule binds, or substantially binds to, human APRIL, butdoes not bind to mouse APRIL, or binds to mouse APRIL with low affinity.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, e.g., between 0.1nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, e.g., 10 nM or less, e.g., 9 nMor less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM orless, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM orless, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less,0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less,0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and 100nM, e.g., between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between0.1 nM and 20 nM, e.g., between 0.1 nM and 10 nM, between 0.5 nM and 5nM, between 1 nM and 5 nM, between 0.001 nM and 0.1 nM, between 0.001 nMand 0.01 nM, between 0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM,or between 0.01 nM and 0.1 nM, e.g., as determined by a method describedherein.

In an embodiment, the antibody molecule does not bind to mouse APRIL, orbinds to mouse APRIL with low affinity, e.g., at an EC₅₀ of 1000 nM ormore, e.g., 2000 nM or more, e.g., as determined by a method describedherein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both). In an embodiment, theantibody molecule inhibits, or substantially inhibits, binding of APRIL(e.g., human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI,mouse TACI, or both), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less,30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less,7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM orless, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less,or 0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and50 nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1nM and 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein.

In an embodiment, binding of the antibody molecule to APRIL (e.g., humanAPRIL) inhibits, or substantially inhibits, the binding of the CRD2domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL). In anembodiment, binding of the antibody molecule to human APRIL inhibits, orsubstantially inhibits, the binding of human TACI, to one or more, e.g.,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, or all, of the human APRIL residues from Table 3. In anembodiment, binding of the antibody molecule to human APRIL, inhibits,or substantially inhibits, the binding of human TACI to one or more,e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all, of the human APRIL residuesfrom Table 4. In an embodiment, binding of the antibody molecule tohuman APRIL inhibits, or substantially inhibits, the binding of humanTACI, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, or all, of the human APRIL residues from Table 7. In anembodiment, binding of the antibody molecule to human APRIL inhibits, orsubstantially inhibits, the binding of human TACI, to one or more, e.g.,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, or all, of the human APRIL residues from Table 8. Inanother embodiment, binding of the antibody molecule to human APRILinhibits, or substantially inhibits, the binding of human BCMA, to oneor more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, or all, of the human APRIL residues fromTable 8.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both). In an embodiment, theantibody molecule inhibits, or substantially inhibits, binding of APRIL(e.g., human APRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA,mouse BCMA, or both), e.g., at an IC₅₀ of 200 nM or less, 150 nM orless, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nMor less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nMor less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM orless, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less,0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, e.g.,between 0.01 nM and 50 nM, between 0.1 nM and 50 nM, between 0.1 nM and25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nMand 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between1 nM and 5 nM, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule is a synthetic antibodymolecule. In an embodiment, the antibody molecule is an isolatedantibody molecule. In an embodiment, the antibody molecule is an IgGantibody molecule, e.g., comprising a heavy chain constant region ofIgG, e.g., chosen from IgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g.,IgG2 or IgG4. In an embodiment, the antibody molecule is an IgG1antibody molecule. In an embodiment, the antibody molecule is an IgG2antibody molecule. In an embodiment, the antibody molecule comprises alight chain constant region of kappa or lambda light chain.

In an embodiment, the antibody molecule comprises an Fc region. In anembodiment, the Fc region comprises one or more mutations located at theinterface between the CH2 and CH3 domains (e.g., to increase the bindingaffinity to neonatal receptor FcRn and/or the half-life of the antibodymolecule). In an embodiment, the Fc region comprises one or moremutations, e.g., one or more (e.g., 2, 3, 4, 6 or all) mutations chosenfrom T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combinationthereof, of IgG1. In an embodiment, the Fc region comprises one or moremutations at positions 233-236 or 322 of human IgG1 or IgG2, or one ormore substitutions at positions 327, 330 or 331 of human IgG4 (e.g., toreduce complement-dependent cytotoxicity (CDC)). In an embodiment, theFc region comprises one or more (e.g., 2, 3, 4, 6 7 or all) mutationschosen from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, orany combination thereof.

In an embodiment, the antibody molecule is a humanized antibodymolecule, e.g., as described in Table 1 or 5, e.g., comprising one ormore framework regions derived from human framework germline sequence.

In an embodiment, the antibody molecule comprises two heavy chainvariable regions and two light chain variable regions. In an embodiment,the antibody molecule is a Fab, F(ab′)2, Fv, Fd, or a single chain Fvfragment (scFv).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO: 1); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2218 (e.g., SEQ ID NO: 2); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2218 (e.g., SEQID NO: 3).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO: 4); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2218 (e.g., SEQ ID NO: 5); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 2218 (e.g., SEQID NO: 6).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 1); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:2); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 3), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 4); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:5); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 1); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:2); and an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 3), and (ii) a VL comprising:an LCDR1 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 4); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:5); and an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In an embodiment, the antibody molecule comprises a VH comprising one,two, or all of the following: (i) an HCDR1 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO:7); (ii) an HCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR2 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 8); or (iii) an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 2218 (e.g., SEQ ID NO: 3).

In an embodiment, the antibody molecule comprises a VL comprising one,two, or all of the following: (i) an LCDR1 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR1 of monoclonal antibody 2218 (e.g., SEQ ID NO:4); (ii) an LCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 5); or (iii) an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2218 (e.g., SEQ ID NO: 6).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 7); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:8); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 3), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 4); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:5); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 6).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 7); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:8); and an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 3), and (ii) a VL comprising:an LCDR1 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2218 (e.g., SEQ ID NO: 4); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO:5); and an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 6). In an embodiment, theantibody molecule comprises a VH comprising an amino acid sequence thatdiffers by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15 amino acid residues from, or has at least 85, 90, 95, 96, 97, 98,99, or 100% homology with, the amino acid sequence of the VH ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 9). In an embodiment, theantibody molecule comprises a VL comprising an amino acid sequence thatdiffers by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15 amino acid residues from, or has at least 85, 90, 95, 96, 97, 98,99, or 100% homology with, the amino acid sequence of the VL ofmonoclonal antibody 2218 (e.g., SEQ ID NO: 10).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2218 (e.g., SEQ ID NO: 9); and(ii) a VL comprising an amino acid sequence that differs by no more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residuesfrom, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with,the amino acid sequence of the VL of monoclonal antibody 2218 (e.g., SEQID NO: 10). In an embodiment, the antibody molecule comprises: (i) a VHcomprising the amino acid sequence of the VH of monoclonal antibody 2218(e.g., SEQ ID NO: 9); and (ii) a VL comprising the amino acid sequenceof the VL of monoclonal antibody 2218 (e.g., SEQ ID NO: 10).

In an embodiment the antibody molecule is monoclonal antibody 2218. Inan embodiment, monoclonal antibody 2218 is a humanized monoclonalantibody 2218. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 190-201, a VLcomprising the amino acid sequence of any of SEQ ID NO: 202-208, orboth.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 11) or a2419-related antibody; (ii) an HCDR2 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 12) or a2419-related antibody; or (iii) an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO:13) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 14) or a2419-related antibody; (ii) an LCDR2 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 15) or a2419-related antibody; or (iii) an LCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO:16) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 11) or a 2419-related antibody; an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2419 (e.g., SEQ ID NO: 12) or a 2419-related antibody; or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody, and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 14) or a 2419-related antibody; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2419 (e.g., SEQ ID NO: 15) or a 2419-related antibody; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2419 (e.g., SEQ ID NO: 16) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 11) or a 2419-related antibody; an HCDR2comprising the amino acid sequence of the HCDR2 of monoclonal antibody2419 (e.g., SEQ ID NO: 12) or a 2419-related antibody; or an HCDR3comprising the amino acid sequence of the HCDR3 of monoclonal antibody2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody, and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2419 (e.g., SEQ ID NO: 14) or a 2419-relatedantibody; an LCDR2 comprising the amino acid sequence of the LCDR2 ofmonoclonal antibody 2419 (e.g., SEQ ID NO: 15) or a 2419-relatedantibody; and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or a 2419-relatedantibody.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 17) or a2419-related antibody; (ii) an HCDR2 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 18) or a2419-related antibody; or (iii) an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO:13) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 14) or a2419-related antibody; (ii) an LCDR2 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 15) or a2419-related antibody; or (iii) an LCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR3 of monoclonal antibody 2419 (e.g., SEQ ID NO:16) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 17) or a 2419-related antibody; an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2419 (e.g., SEQ ID NO: 18) or a 2419-related antibody; or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody, and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 14) or a 2419-related antibody; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2419 (e.g., SEQ ID NO: 15) or a 2419-related antibody; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2419 (e.g., SEQ ID NO: 16) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2419 (e.g., SEQ ID NO: 17) or a 2419-related antibody; an HCDR2comprising the amino acid sequence of the HCDR2 of monoclonal antibody2419 (e.g., SEQ ID NO: 18) or a 2419-related antibody; or an HCDR3comprising the amino acid sequence of the HCDR3 of monoclonal antibody2419 (e.g., SEQ ID NO: 13) or a 2419-related antibody, and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2419 (e.g., SEQ ID NO: 14) or a 2419-relatedantibody; an LCDR2 comprising the amino acid sequence of the LCDR2 ofmonoclonal antibody 2419 (e.g., SEQ ID NO: 15) or a 2419-relatedantibody; and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2419 (e.g., SEQ ID NO: 16) or a 2419-relatedantibody.

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2419 (e.g., SEQ ID NO: 19) ora 2419-related antibody. In an embodiment, the antibody moleculecomprises a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2419 (e.g., SEQ ID NO: 20) or a 2419-related antibody.

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2419 (e.g., SEQ ID NO: 19) ora 2419-related antibody; and (ii) a VL comprising an amino acid sequencethat differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, or 15 amino acid residues from, or has at least 85, 90, 95, 96, 97,98, 99, or 100% homology with, the amino acid sequence of the VL ofmonoclonal antibody 2419 (e.g., SEQ ID NO: 20) or a 2419-relatedantibody.

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthe amino acid sequence of the VH of monoclonal antibody 2419 (e.g., SEQID NO: 19) or a 2419-related antibody; and (ii) a VL comprising theamino acid sequence of the VL of monoclonal antibody 2419 (e.g., SEQ IDNO: 20) or a 2419-related antibody.

In an embodiment the antibody molecule is monoclonal antibody 2419. Inan embodiment, monoclonal antibody 2419 is a humanized monoclonalantibody 2419. In an embodiment, the antibody molecule is a 2419-relatedantibody molecule, e.g., any of antibodies 2419-0105, 2419-0205,2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, or 2419-1406,e.g., as disclosed in Table 1 or 5. In an embodiment, the antibodymolecule comprises a VH comprising the amino acid sequence of any of SEQID NOS: 209-214, 283, 288, 289, 291, 292, 294, 296, or 317, a VLcomprising the amino acid sequence of any of SEQ ID NOS: 215-219, 284,286, 295, or 316, or both.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 21); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2922 (e.g., SEQ ID NO: 32); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2922 (e.g., SEQID NO: 33).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2922 (e.g., SEQ ID NO: 35); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 2922 (e.g., SEQID NO: 36).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 21); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO:32); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 33), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 34); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO:35); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 21); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 32);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 33), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 34); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 2922 (e.g., SEQID NO: 35); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 37); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2922 (e.g., SEQ ID NO: 38); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2922 (e.g., SEQID NO: 33).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 34); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2922 (e.g., SEQ ID NO: 35); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 2922 (e.g., SEQID NO: 36).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 37); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO:38); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 33), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 34); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO:35); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2922 (e.g., SEQ ID NO: 37); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 38);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 33), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 34); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 2922 (e.g., SEQID NO: 35); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2922 (e.g., SEQ ID NO: 36).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 2922 (e.g., SEQ ID NO: 40).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2922 (e.g., SEQ ID NO: 39);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2922 (e.g., SEQ ID NO: 40). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 2922 (e.g., SEQ ID NO: 39); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 2922 (e.g., SEQID NO: 40).

In an embodiment the antibody molecule is monoclonal antibody 2922. Inan embodiment, the antibody molecule is a humanized monoclonal antibody2922.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 51); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3327 (e.g., SEQ ID NO: 52); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3327 (e.g., SEQID NO: 53).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 54); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3327 (e.g., SEQ ID NO: 55); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3327 (e.g., SEQID NO: 56).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 51); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO:52); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 53), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 54); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO:55); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 51); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 52);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 53), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 54); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3327 (e.g., SEQID NO: 55); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 57); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3327 (e.g., SEQ ID NO: 58); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3327 (e.g., SEQID NO: 53).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3327 (e.g., SEQ ID NO: 54); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3327 (e.g., SEQ ID NO: 55); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3327 (e.g., SEQID NO: 56).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 57); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO:58); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 53), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 54); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO:55); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3327 (e.g., SEQ ID NO: 57); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 58);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 53), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 54); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3327 (e.g., SEQID NO: 55); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3327 (e.g., SEQ ID NO: 56).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3327 (e.g., SEQ ID NO: 60).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3327 (e.g., SEQ ID NO: 59);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3327 (e.g., SEQ ID NO: 60). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3327 (e.g., SEQ ID NO: 59); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3327 (e.g., SEQID NO: 60).

In an embodiment the antibody molecule is monoclonal antibody 3327. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3327.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 61); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 62); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 61); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:62); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 61); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 62);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 64); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3530 (e.g., SEQ ID NO: 67); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3530 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3530 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 64); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:65); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3530 (e.g., SEQ ID NO: 64); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 65);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 67); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3530 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3530 (e.g., SEQ ID NO: 70).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3530 (e.g., SEQ ID NO: 66);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3530 (e.g., SEQ ID NO: 70). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3530 (e.g., SEQ ID NO: 66); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3530 (e.g., SEQID NO: 70).

In an embodiment the antibody molecule is monoclonal antibody 3530. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3530.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 62); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising: an HCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 61); an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 62); or an HCDR3 comprising an aminoacid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 63), and

(ii) a VL comprising: an LCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 45); or an LCDR3 comprising an aminoacid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 61); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 64); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 65); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 63).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3525 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3525 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3525 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 64); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:65); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3525 (e.g., SEQ ID NO: 64); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 65);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 63), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 44); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3525 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3525 (e.g., SEQ ID NO: 50).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3525 (e.g., SEQ ID NO: 66);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3525 (e.g., SEQ ID NO: 50). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3525 (e.g., SEQ ID NO: 66); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3525 (e.g., SEQID NO: 50).

In an embodiment the antibody molecule is monoclonal antibody 3525. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3525.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 21); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2621 (e.g., SEQ ID NO: 22); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2621 (e.g., SEQID NO: 23).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 24); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2621 (e.g., SEQ ID NO: 25); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 2621 (e.g., SEQID NO: 26).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 21); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO:22); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 23), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 24); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO:25); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 21); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 22);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 23), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 24); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 2621 (e.g., SEQID NO: 25); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 27); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2621 (e.g., SEQ ID NO: 28); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2621 (e.g., SEQID NO: 23).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 2621 (e.g., SEQ ID NO: 24); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 2621 (e.g., SEQ ID NO: 25); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 2621 (e.g., SEQID NO: 26).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 27); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO:28); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 23), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 24); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO:25); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 2621 (e.g., SEQ ID NO: 27); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 28);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 23), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 24); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 2621 (e.g., SEQID NO: 25); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 2621 (e.g., SEQ ID NO: 26).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 2621 (e.g., SEQ ID NO: 30).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 2621 (e.g., SEQ ID NO: 29);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2621 (e.g., SEQ ID NO: 30). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 2621 (e.g., SEQ ID NO: 29); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 2621 (e.g., SEQID NO: 30).

In an embodiment the antibody molecule is monoclonal antibody 2621. Inan embodiment, the antibody molecule is a humanized monoclonal antibody2621.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 11); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3125 (e.g., SEQ ID NO: 42); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3125 (e.g., SEQID NO: 43).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3125 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3125 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 11); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO:42); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 43), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 11); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 42);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 43), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 44); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3125 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 47); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3125 (e.g., SEQ ID NO: 48); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3125 (e.g., SEQID NO: 43).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3125 (e.g., SEQ ID NO: 44); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3125 (e.g., SEQ ID NO: 45); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3125 (e.g., SEQID NO: 46).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 47); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO:48); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 43), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3125 (e.g., SEQ IDNO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3125 (e.g., SEQ ID NO: 47); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 48);and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 43), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 44); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3125 (e.g., SEQID NO: 45); and an LCDR3 comprising the amino acid sequence of the LCDR3of monoclonal antibody 3125 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 3125 (e.g., SEQ ID NO: 50).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3125 (e.g., SEQ ID NO: 49);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3125 (e.g., SEQ ID NO: 50). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3125 (e.g., SEQ ID NO: 49); and (ii) a VL comprisingthe amino acid sequence of the VL of monoclonal antibody 3125 (e.g., SEQID NO: 50).

In an embodiment the antibody molecule is monoclonal antibody 3125. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3125.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:93); (ii) an HCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR2 ofmonoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 94); or (iii) anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 95).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:96); (ii) an LCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); or (iii) anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 93); an HCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR2 of monoclonal antibody 4035 or 4035-062(e.g., SEQ ID NO: 94); or an HCDR3 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:95), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 96); an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR2 of monoclonal antibody 4035 or 4035-062(e.g., SEQ ID NO: 97); or an LCDR3 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:98).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 93); an HCDR2 comprising theamino acid sequence of the HCDR2 of monoclonal antibody 4035 or 4035-062(e.g., SEQ ID NO: 94); and an HCDR3 comprising the amino acid sequenceof the HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:95), and (ii) a VL comprising: an LCDR1 comprising the amino acidsequence of the LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQID NO: 96); an LCDR2 comprising the amino acid sequence of the LCDR2 ofmonoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); and an LCDR3comprising the amino acid sequence of the LCDR3 of monoclonal antibody4035 or 4035-062 (e.g., SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:99); (ii) an HCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR2 ofmonoclonal antibody 4035 (e.g., SEQ ID NO: 100) or 4035-062 (e.g., SEQID NO: 273); or (iii) an HCDR3 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 95).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:96); (ii) an LCDR2 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO: 97); or (iii) anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 99); an HCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR2 of monoclonal antibody 4035 (e.g., SEQID NO: 100) or 4035-062 (e.g., SEQ ID NO: 273); or an HCDR3 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the HCDR3 of monoclonal antibody 4035or 4035-062 (e.g., SEQ ID NO: 95), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 96); an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR2 of monoclonal antibody 4035 or 4035-062(e.g., SEQ ID NO: 97); or an LCDR3 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:98).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4035 or 4035-062 (e.g., SEQ ID NO: 99); an HCDR2 comprising theamino acid sequence of the HCDR2 of monoclonal antibody 4035 (e.g., SEQID NO: 100) or 4035-062 (e.g., SEQ ID NO: 273); and an HCDR3 comprisingthe amino acid sequence of the HCDR3 of monoclonal antibody 4035 or4035-062 (e.g., SEQ ID NO: 95), and (ii) a VL comprising: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody4035 or 4035-062 (e.g., SEQ ID NO: 96); an LCDR2 comprising the aminoacid sequence of the LCDR2 of monoclonal antibody 4035 or 4035-062(e.g., SEQ ID NO: 97); and an LCDR3 comprising the amino acid sequenceof the LCDR3 of monoclonal antibody 4035 or 4035-062 (e.g., SEQ ID NO:98).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or4035-062 (e.g., SEQ ID NO: 225). In an embodiment, the antibody moleculecomprises a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4035 (e.g., SEQ ID NO: 101) or4035-062 (e.g., SEQ ID NO: 225); and (ii) a VL comprising an amino acidsequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15 amino acid residues from, or has at least 85, 90, 95,96, 97, 98, 99, or 100% homology with, the amino acid sequence of the VLof monoclonal antibody 4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g.,SEQ ID NO: 229). In an embodiment, the antibody molecule comprises: (i)a VH comprising the amino acid sequence of the VH of monoclonal antibody4035 (e.g., SEQ ID NO: 101) or 4035-062 (e.g., SEQ ID NO: 225); and (ii)a VL comprising the amino acid sequence of the VL of monoclonal antibody4035 (e.g., SEQ ID NO: 102) or 4035-062 (e.g., SEQ ID NO: 229).

In an embodiment, the antibody molecule is monoclonal antibody 4035. Inan embodiment, monoclonal antibody 4035 is a humanized monoclonalantibody 4035 (e.g., antibody 4035-062). In another embodiment, theantibody molecule is antibody 4035-062. In an embodiment, the antibodymolecule comprises a VH comprising the amino acid sequence of any of SEQID NOS: 220-227 or 262-265, a VL comprising the amino acid sequence ofany of SEQ ID NOS: 228-234, or both.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 103); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3934 (e.g., SEQ ID NO: 104); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3934 (e.g., SEQID NO: 105).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 106); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3934 (e.g., SEQ ID NO: 107); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3934 (e.g., SEQID NO: 108).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 103); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:104); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 105), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 106); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:107); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 103); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:104); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 105), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 106); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3934 (e.g., SEQID NO: 107); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 109); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3934 (e.g., SEQ ID NO: 110); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3934 (e.g., SEQID NO: 105).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3934 (e.g., SEQ ID NO: 106); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3934 (e.g., SEQ ID NO: 107); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3934 (e.g., SEQID NO: 108).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 109); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:110); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 105), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 106); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:107); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3934 (e.g., SEQ ID NO: 109); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO:110); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 105), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 106); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3934 (e.g., SEQID NO: 107); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3934 (e.g., SEQ ID NO: 108).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3934 (e.g., SEQ ID NO: 112).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3934 (e.g., SEQ ID NO: 111);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3934 (e.g., SEQ ID NO: 112). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3934 (e.g., SEQ ID NO: 111); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3934(e.g., SEQ ID NO: 112).

In an embodiment the antibody molecule is monoclonal antibody 3934. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3934.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 112); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 113); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 114).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 115); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 116); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 117).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 113); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:114); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:117); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 113); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:114); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQID NO: 117); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 119); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 120); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 115).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3833 (e.g., SEQ ID NO: 116); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3833 (e.g., SEQ ID NO: 117); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3833 (e.g., SEQID NO: 118).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 119); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:120); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:117); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3833 (e.g., SEQ ID NO: 119); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO:120); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 115), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 116); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3833 (e.g., SEQID NO: 117); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3833 (e.g., SEQ ID NO: 122).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3833 (e.g., SEQ ID NO: 121);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3833 (e.g., SEQ ID NO: 122). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3833 (e.g., SEQ ID NO: 121); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3833(e.g., SEQ ID NO: 122).

In an embodiment the antibody molecule is monoclonal antibody 3833. Inan embodiment, monoclonal antibody 3833 is a humanized monoclonalantibody 3833. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 246-250, a VLcomprising the amino acid sequence of any of SEQ ID NO: 251-253, orboth.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 123); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 124); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 125).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 128).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 123); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:124); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 123); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:124); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 129); anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 130); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 125).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3631 (e.g., SEQ ID NO: 126); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3631 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3631 (e.g., SEQID NO: 128).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 129); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:130); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQ IDNO:45); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3631 (e.g., SEQ ID NO: 129); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO:130); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 125), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 126); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3631 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3631 (e.g., SEQ ID NO: 132).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3631 (e.g., SEQ ID NO: 131);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3631 (e.g., SEQ ID NO: 132). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3631 (e.g., SEQ ID NO: 131); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3631(e.g., SEQ ID NO: 132).

In an embodiment the antibody molecule is monoclonal antibody 3631. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3631.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 133); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 134); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 135).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 137).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 133); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:134); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 133); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:134); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 138); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 139); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 135).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 3732 (e.g., SEQ ID NO: 136); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 3732 (e.g., SEQ ID NO: 127); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 3732 (e.g., SEQID NO: 137).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 138); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:139); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:127); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 3732 (e.g., SEQ ID NO: 138); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO:139); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 135), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 136); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 3732 (e.g., SEQID NO: 127); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 3732 (e.g., SEQ ID NO: 141).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 3732 (e.g., SEQ ID NO: 140);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3732 (e.g., SEQ ID NO: 141). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 3732 (e.g., SEQ ID NO: 140); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 3732(e.g., SEQ ID NO: 141).

In an embodiment the antibody molecule is monoclonal antibody 3732. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3732.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 11); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4338 (e.g., SEQ ID NO: 142); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 4338 (e.g., SEQID NO: 143).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 144 or 146);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or (iii) anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4338 (e.g., SEQ ID NO: 145 or 148).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 11); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:142); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 143), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 144 or 146); an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR2 of monoclonal antibody 4338 (e.g., SEQID NO: 107 or 147); or an LCDR3 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 11); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:142); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 143), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 144 or 146); an LCDR2comprising the amino acid sequence of the LCDR2 of monoclonal antibody4338 (e.g., SEQ ID NO: 107 or 147); and an LCDR3 comprising the aminoacid sequence of the LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO:145 or 148).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 149); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4338 (e.g., SEQ ID NO: 150); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 4338 (e.g., SEQID NO: 143).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4338 (e.g., SEQ ID NO: 144 or 146);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 107 or 147); or (iii) anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4338 (e.g., SEQ ID NO: 145 or 148).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 149); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:150); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 143), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 144 or 146); an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR2 of monoclonal antibody 4338 (e.g., SEQID NO:107 or 147); or an LCDR3 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4338 (e.g., SEQ ID NO: 149); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:150); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 143), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 4338 (e.g., SEQ ID NO: 144 or 146); an LCDR2comprising the amino acid sequence of the LCDR2 of monoclonal antibody4338 (e.g., SEQ ID NO: 107 or 147); and an LCDR3 comprising the aminoacid sequence of the LCDR3 of monoclonal antibody 4338 (e.g., SEQ ID NO:145 or 148).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4338 (e.g., SEQ ID NO: 151).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 4338 (e.g., SEQ ID NO: 152 or153).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4338 (e.g., SEQ ID NO: 151);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4338 (e.g., SEQ ID NO: 152 or 153). In an embodiment, the antibodymolecule comprises: (i) a VH comprising the amino acid sequence of theVH of monoclonal antibody 4338 (e.g., SEQ ID NO: 150); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 4338(e.g., SEQ ID NO: 152 or 153).

In an embodiment the antibody molecule is monoclonal antibody 4338. Inan embodiment, the antibody molecule is a humanized monoclonal antibody4338.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g.,SEQ ID NO: 154); (ii) an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQID NO: 155); or (iii) an HCDR3 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQID NO: 156).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116),4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ IDNO: 275), or 4540-033 (e.g., SEQ ID NO: 275); or (iii) an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 154); an HCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 155); or an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274),or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises: an HCDR1comprises the amino acid sequence of the HCDR1 of monoclonal antibody4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 154); an HCDR2 comprisingthe amino acid sequence of the HCDR2 of monoclonal antibody 4540,4540-063, or 4540-033 (e.g., SEQ ID NO: 155); and an HCDR3 comprisingthe amino acid sequence of the HCDR3 of monoclonal antibody 4540,4540-063, or 4540-033 (e.g., SEQ ID NO: 156), and (ii) a light chainvariable region (VL), wherein the light chain variable region comprisesthree light chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises: an LCDR1comprising the amino acid sequence of the LCDR1 of monoclonal antibody4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274), or4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising the amino acidsequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); and an LCDR3 comprising the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 159),4540-063 (e.g., SEQ ID NO: 276), or 4540-033 (e.g., SEQ ID NO: 159);(ii) an HCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (e.g., SEQ IDNO: 277), or 4540-033 (e.g., SEQ ID NO: 278); or (iii) an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116),4540-063 (e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274);(ii) an LCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the LCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ IDNO: 275), or 4540-033 (e.g., SEQ ID NO: 275); or (iii) an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 159), 4540-063 (e.g., SEQ ID NO: 276),or 4540-033 (e.g., SEQ ID NO: 159); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:160), 4540-063 (e.g., SEQ ID NO: 277), or 4540-033 (e.g., SEQ ID NO:278); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 156),and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4540 (e.g., SEQ ID NO: 116), 4540-063 (e.g., SEQ ID NO: 274),or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO:157), 4540-063 (e.g., SEQ ID NO: 275), or 4540-033 (e.g., SEQ ID NO:275); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4540, 4540-063, or 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingone, two, or all of the following: an HCDR1 comprising the amino acidsequence of the HCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO:159), 4540-063 (e.g., SEQ ID NO: 276), or 4540-033 (e.g., SEQ ID NO:159); an HCDR2 comprising the amino acid sequence of the HCDR2 ofmonoclonal antibody 4540 (e.g., SEQ ID NO: 160), 4540-063 (e.g., SEQ IDNO: 277), or 4540-033 (e.g., SEQ ID NO: 278); or an HCDR3 comprising theamino acid sequence of the HCDR3 of monoclonal antibody 4540, 4540-063,or 4540-033 (e.g., SEQ ID NO: 156), and (ii) a VL comprising one, two,or all of the following: an LCDR1 comprising the amino acid sequence ofthe LCDR1 of monoclonal antibody 4540 (e.g., SEQ ID NO: 116), 4540-063(e.g., SEQ ID NO: 274), or 4540-033 (e.g., SEQ ID NO: 274); an LCDR2comprising the amino acid sequence of the LCDR2 of monoclonal antibody4540 (e.g., SEQ ID NO: 157), 4540-063 (e.g., SEQ ID NO: 275), or4540-033 (e.g., SEQ ID NO: 275); or an LCDR3 comprising the amino acidsequence of the LCDR3 of monoclonal antibody 4540, 4540-063, or 4540-033(e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4540 (e.g., SEQ ID NO: 161),4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256). Inan embodiment, the antibody molecule comprises a VL comprising an aminoacid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least 85,90, 95, 96, 97, 98, 99, or 100% homology with, the amino acid sequenceof the VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063(e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4540 (e.g., SEQ ID NO: 161),4540-063 (e.g., SEQ ID NO: 258), or 4540-033 (e.g., SEQ ID NO: 256); and(ii) a VL comprising an amino acid sequence that differs by no more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residuesfrom, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with,the amino acid sequence of the VL of monoclonal antibody 4540 (e.g., SEQID NO: 162), 4540-063 (e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ IDNO: 261). In an embodiment, the antibody molecule comprises: (i) a VHcomprising the amino acid sequence of the VH of monoclonal antibody 4540(e.g., SEQ ID NO: 161), 4540-063 (e.g., SEQ ID NO: 258), or 4540-033(e.g., SEQ ID NO: 256); and (ii) a VL comprising the amino acid sequenceof the VL of monoclonal antibody 4540 (e.g., SEQ ID NO: 162), 4540-063(e.g., SEQ ID NO: 261), or 4540-033 (e.g., SEQ ID NO: 261).

In an embodiment the antibody molecule is monoclonal antibody 4540,4540-063, or 4540-033. In an embodiment, monoclonal antibody 4540 is ahumanized monoclonal antibody 4540 (e.g., antibodies 4540-063 or4540-033). In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NOS: 254-258, a VLcomprising the amino acid sequence of any of SEQ ID NOS: 259-261, orboth.

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 163); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4237 (e.g., SEQ ID NO: 164); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 4237 (e.g., SEQID NO: 165).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 4237 (e.g., SEQ ID NO: 167); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 4237 (e.g., SEQID NO: 168).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 163); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:164); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 165), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 166); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:167); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 163); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:164); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 165), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 166); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 4237 (e.g., SEQID NO: 167); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In an embodiment, the antibody molecule comprises a heavy chain variableregion (VH), wherein the heavy chain variable region comprises threeheavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: (i) an HCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 169); (ii) anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4237 (e.g., SEQ ID NO: 170); or (iii) an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 4237 (e.g., SEQID NO: 165).

In an embodiment, the antibody molecule comprises a light chain variableregion (VL), wherein the light chain variable region comprises threelight chain complementarity determining regions (LCDR1, LCDR2, andLCDR3), wherein the light chain variable region comprises one, two, orall of the following: (i) an LCDR1 comprising an amino acid sequencethat differs by no more than 1, 2, or 3 amino acid residues from, or hasat least 85, 90, 95, 99 or 100% homology with, the amino acid sequenceof the LCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 166); (ii) anLCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR2 of monoclonalantibody 4237 (e.g., SEQ ID NO: 167); or (iii) an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the LCDR3 of monoclonal antibody 4237 (e.g., SEQID NO: 168).

In an embodiment, the antibody molecule comprises:

(i) a VH comprising one, two, or all of the following: an HCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 169); an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:170); or an HCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 165), and

(ii) a VL comprising one, two, or all of the following: an LCDR1comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 166); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:167); or an LCDR3 comprising an amino acid sequence that differs by nomore than 1, 2, or 3 amino acid residues from, or has at least 85, 90,95, 99 or 100% homology with, the amino acid sequence of the LCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In an embodiment, the antibody molecule comprises: (i) a VH comprising:an HCDR1 comprising the amino acid sequence of the HCDR1 of monoclonalantibody 4237 (e.g., SEQ ID NO: 169); an HCDR2 comprising the amino acidsequence of the HCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO:170); and an HCDR3 comprising the amino acid sequence of the HCDR3 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 165), and (ii) a VLcomprising: an LCDR1 comprising the amino acid sequence of the LCDR1 ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 166); an LCDR2 comprising theamino acid sequence of the LCDR2 of monoclonal antibody 4237 (e.g., SEQID NO: 167); and an LCDR3 comprising the amino acid sequence of theLCDR3 of monoclonal antibody 4237 (e.g., SEQ ID NO: 168).

In an embodiment, the antibody molecule comprises a VH comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171).In an embodiment, the antibody molecule comprises a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of monoclonal antibody 4237 (e.g., SEQ ID NO: 172).

In an embodiment, the antibody molecule comprises: (i) a VH comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VH of monoclonal antibody 4237 (e.g., SEQ ID NO: 171);and (ii) a VL comprising an amino acid sequence that differs by no morethan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidresidues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4237 (e.g., SEQ ID NO: 172). In an embodiment, the antibody moleculecomprises: (i) a VH comprising the amino acid sequence of the VH ofmonoclonal antibody 4237 (e.g., SEQ ID NO: 171); and (ii) a VLcomprising the amino acid sequence of the VL of monoclonal antibody 4237(e.g., SEQ ID NO: 172).

In an embodiment the antibody molecule is monoclonal antibody 4237. Inan embodiment, monoclonal antibody 4237 is a humanized monoclonalantibody 4237. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NOS: 235-240, a VLcomprising the amino acid sequence of any of SEQ ID NOS: 241-245, orboth.

In another aspect, the disclosure features an anti-APRIL antibodymolecule, which:

(i) binds, or substantially binds, to human APRIL;

(ii) inhibits, or substantially inhibits, binding of APRIL (e.g., humanAPRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouse TACI, orboth);

(iii) inhibits, or substantially inhibits, binding of APRIL (e.g., humanAPRIL, mouse APRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, orboth); and

(iv) binds, or substantially binds, to one or more, e.g., 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,or more, residues within a region of human APRIL as defined in any ofTables 3-4 or 7-8.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein.

In an embodiment, the antibody molecule does not bind to mouse APRIL, orbinds to mouse APRIL with low affinity, e.g., at an EC₅₀ of 1000 nM ormore, e.g., 2000 nM or more, e.g., as determined by a method describedherein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), e.g., at an IC₅₀ of 200 nMor less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less,30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less,7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM orless, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less,0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nMand 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein.

In an embodiment, the antibody molecule binds, or substantially binds,to an epitope that comprises APRIL residues from two monomers, e.g., oneor more residues from monomer A and monomer B as shown in Table 3. In anembodiment, the antibody molecule binds, or substantially binds, to oneor more APRIL residues from the C-D loop (e.g., the loop connectingβ-sheets C and D), the G-H loop (e.g., the loop connecting β-sheets Gand H), or both. In an embodiment, the antibody molecule binds, orsubstantially binds, to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, orall) residues of human APRIL from positions 105-114 and/or one or more(e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of mouse APRIL frompositions 96-105. In an embodiment, the antibody molecule does not bind,or binds with low affinity, to one, two or all of Asp129, Arg233, orHis203 of human APRIL.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH) comprising one, two, or all ofthe following: an HCDR1 comprising an amino acid sequence that differsby no more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the HCDR1of a monoclonal antibody chosen from antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3125, 2621, 4035, 4035-062, 3934, 4338, 4439, or4237; an HCDR2 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR2 of the(same) monoclonal antibody; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the HCDR3 of the (same) monoclonal antibody, or

(ii) a light chain variable region (VL) comprising one, two, or all ofthe following: an LCDR1 comprising an amino acid sequence that differsby no more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the LCDR1of the (same) monoclonal antibody; an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of the (same) monoclonal antibody; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of the (same)monoclonal antibody.

In an embodiment, the antibody molecule comprises one or both of:

(i) a VH comprising an amino acid sequence that differs by no more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residuesfrom, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with,the amino acid sequence of the VH of a monoclonal antibody chosen fromantibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210,2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3125, 2621,4035, 4035-062, 3934, 4338, 4439, or 4237; or

(ii) a VL comprising an amino acid sequence that differs by no more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residuesfrom, or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with,the amino acid sequence of the VL of the (same) monoclonal antibody. Inan embodiment, the antibody molecule is a synthetic antibody molecule.In an embodiment, the antibody molecule is an isolated antibodymolecule. In an embodiment, the antibody molecule is a humanizedantibody molecule, e.g., comprising one or more framework regionsderived from human framework germline sequence.

In an embodiment, the antibody molecule is an IgG antibody molecule,e.g., comprising a heavy chain constant region of IgG, e.g., chosen fromIgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In anembodiment, the antibody molecule is an IgG1 antibody molecule. In anembodiment, the antibody molecule is an IgG2 antibody molecule. In anembodiment, the antibody molecule comprises a light chain constantregion of kappa or lambda light chain.

In an embodiment, the antibody molecule comprises an Fc region. In anembodiment, the Fc region comprises one or more mutations located at theinterface between the CH2 and CH3 domains (e.g., to increase the bindingaffinity to neonatal receptor FcRn and/or the half-life of the antibodymolecule). In an embodiment, the Fc region comprises one or moremutations, e.g., one or more (e.g., 2, 3, 4, 6 or all) mutations chosenfrom T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combinationthereof, of IgG1. In an embodiment, the Fc region comprises one or moremutations at positions 233-236 or 322 of human IgG1 or IgG2, or one ormore substitutions at positions 327, 330 or 331 of human IgG4 (e.g., toreduce complement-dependent cytotoxicity (CDC)). In an embodiment, theFc region comprises one or more (e.g., 2, 3, 4, 6 7 or all) mutationschosen from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, orany combination thereof.

In an embodiment, the antibody molecule comprises two heavy chainvariable regions and two light chain variable regions. In an embodiment,the antibody molecule is a Fab, F(ab′)2, Fv, Fd, or a single chain Fvfragment (scFv).

In an aspect, the disclosure features an anti-APRIL antibody, which:

a) competes for binding to APRIL with an antibody molecule comprisingthe heavy chain complementary determining regions (HCDR1, HCDR2 andHCDR3) and the light chain complementary determining regions (LCDR1,LCDR2 and LCDR3) of any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or 4237, e.g.,as described in Table 1 or 5; or

b) binds, or substantially binds, to an epitope that completely orpartially overlaps with the epitope of an antibody molecule comprisingthe heavy chain complementary determining regions (HCDR1, HCDR2 andHCDR3) and the light chain complementary determining regions (LCDR1,LCDR2 and LCDR3) of any of monoclonal antibodies 2218 (e.g., SEQ ID NOS:1-6 according to Chothia numbering or SEQ ID NOS: 3-8 according to Kabatnumbering), 2419 (e.g., SEQ ID NOS: 11-16 according to Chothia numberingor SEQ ID NOS: 13-18 according to Kabat numbering), 2419-0105 (e.g., SEQID NOS: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ IDNOS: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-0205(e.g., SEQ ID NOS: 11-13, 16, 280 and 281 according to Chothia numberingor SEQ ID NOS: 13, 16, 17 and 280-282 according to Kabat numbering),2419-0206 (e.g., SEQ ID NOS: 11-13, 16, 280 and 285 according to Chothianumbering or SEQ ID NOS: 13, 16, 17, 280, 282 and 285 according to Kabatnumbering), 2419-0406 (e.g., SEQ ID NOS: 11-13, 16, 280 and 285according to Chothia numbering or SEQ ID NOS: 13, 16, 17, 280, 285 and290 according to Kabat numbering), 2419-0605 (e.g., SEQ ID NOS: 11-13,16, 280 and 281 according to Chothia numbering or SEQ ID NOS: 13, 16, 17and 280-282 according to Kabat numbering), 2419-0805 (e.g., SEQ ID NOS:11-13, 16, 280 and 281 according to Chothia numbering or SEQ ID NOS: 13,16, 17, 280, 281 and 287 according to Kabat numbering), 2419-0806 (e.g.,SEQ ID NOS: 11-13, 16, 280 and 285 according to Chothia numbering or SEQID NOS: 13, 16, 17, 280, 285 and 287 according to Kabat numbering),2419-1204 (e.g., SEQ ID NOS: 11-13, 16, 280 and 293 according to Chothianumbering or SEQ ID NOS: 13, 16, 17, 280, 282 and 293 according to Kabatnumbering), 2419-1205 (e.g., SEQ ID NOS: 11-13, 16, 280 and 281according to Chothia numbering or SEQ ID NOS: 13, 16, 17 and 280-282according to Kabat numbering), 2419-1210 (e.g., SEQ ID NOS: 11-13, 16,314 and 315 according to Chothia numbering or SEQ ID NOS: 13, 16, 17,282, 314 and 315 according to Kabat numbering), 2419-1305 (e.g., SEQ IDNOS: 11-13, 16, 280 and 281 according to Chothia numbering or SEQ IDNOS: 13, 16, 17 and 280-282 according to Kabat numbering), 2419-1306(e.g., SEQ ID NOS: 11-13, 16, 280 and 285 according to Chothia numberingor SEQ ID NOS: 13, 16, 17, 280, 282 and 285 according to Kabatnumbering), 2419-1310 (e.g., SEQ ID NOS: 11-13, 16, 314 and 315according to Chothia numbering or SEQ ID NOS: 13, 16, 17, 282, 314 and315 according to Kabat numbering), 2419-1406 (e.g., SEQ ID NOS: 11-13,16, 280 and 285 according to Chothia numbering or SEQ ID NOS: 13, 16,17, 280, 282 and 285 according to Kabat numbering), 2922 (e.g., SEQ IDNOS: 21 and 32-36 according to Chothia numbering or SEQ ID NOS: 33-38according to Kabat numbering), 3327 (e.g., SEQ ID NOS: 51-56 accordingto Chothia numbering or SEQ ID NOS: 53-58 according to Kabat numbering),3530 (e.g., SEQ ID NOS: 61-63, 67, 45 and 46 according to Chothianumbering or SEQ ID NOS: 63-65, 67, 45 and 46 according to Kabatnumbering), 3525 (e.g., SEQ ID NOS: 44-46 and 61-63 according to Chothianumbering or SEQ ID NOS: 44-46 and 63-65 according to Kabat numbering),3125 (e.g., SEQ ID NOS: 11 and 42-46 according to Chothia numbering orSEQ ID NOS: 43-48 according to Kabat number), 2621 (e.g., SEQ ID NOS:21-26 according to Chothia numbering or SEQ ID NOS: 23-28 according toKabat numbering), 4035 (e.g., SEQ ID NOS: 93-98 according to Chothianumbering or SEQ ID NOS: 95-100 according to Kabat numbering), 4035-062(e.g., SEQ ID NOS: 93-98 according to Chothia numbering or SEQ ID NOS:95-99 and 273 according to Kabat numbering), 3934 (e.g., SEQ ID NOS:103-108 according to Chothia numbering or SEQ ID NOS: 105-110 accordingto Kabat numbering), 3833 (e.g., SEQ ID NOS: 113-118 according toChothia numbering or SEQ ID NOS: 115-120 according to Kabat numbering),3631 (e.g., SEQ ID NOS: 123-128 according to Chothia numbering or SEQ IDNOS: 125-130 according to Kabat numbering), 3732 (e.g., SEQ ID NOS: 127and 133-137 according to Chothia numbering or SEQ ID NOS: 127 and135-139 according to Kabat numbering), 4338 (e.g., SEQ ID NOS: 11, 107and 142-145, or SEQ ID NO: 11, 142, 143 and 146-148 according to Chothianumbering; or SEQ ID NOS: 107, 143-145 and 149-150, or SEQ ID NOS: 143and 146-150 according to Kabat numbering), 4540 (e.g., SEQ ID NOS: 116and 154-158 according to Chothia numbering or SEQ ID NOS: 116 and156-160 according to Kabat numbering), 4540-063 (e.g., SEQ ID NOS:154-156, 158, 274 and 275 according to Chothia numbering or SEQ ID NOS:156, 158 and 274-277 according to Kabat numbering), 4540-033 (e.g., SEQID NOS: 154-156, 158, 274 and 275 according to Chothia numbering or SEQID NOS: 156, 158, 159, 274, 275 and 278 according to Kabat numbering),4439 (e.g., SEQ ID NOS: 146-148 and 266-268 according to Chothianumbering or SEQ ID NOS: 146-148 and 269-270 according to Kabatnumbering), or 4237 (e.g., SEQ ID NOS: 163-168 according to Chothianumbering or SEQ ID NOS: 165-170 according to Kabat numbering), e.g., asdescribed in Table 1 or 5.

In an embodiment, the antibody molecule is a synthetic antibodymolecule. In an embodiment, the antibody molecule is an isolatedantibody molecule.

In an embodiment, the antibody molecule competes for binding with two,three, four, five, six, seven, eight, nine, ten, or more of the antibodymolecules that comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3of any of monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205,2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922,3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732,4338, 4540, 4540-063, 4540-033, 4439, or 4237.

In an embodiment, the antibody molecule binds, or substantially binds,to an epitope that completely or partially overlaps with the epitopes oftwo, three, four, five, six, seven, eight, nine, ten, or more of theantibody molecules that comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2,and LCDR3 of any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, or 4237.

In an embodiment, the antibody molecule that comprises the HCDR1, HCDR2,HCDR3, LCDR1, LCDR2, and LCDR3 of any of monoclonal antibodies 2218,2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 3934,3833, 3631, 3732, 4338, 4540, 4439, or 4237 comprises a heavy chainvariable region and a light chain variable region of any of monoclonalantibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210,2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525,3125, 2621, 4035, 3934, 3833, 3631, 3732, 4338, 4540, 4439, or 4237.

In an embodiment, the antibody molecule that comprises the HCDR1, HCDR2,HCDR3, LCDR1, LCDR2, and LCDR3 of any of monoclonal antibodies 2218,2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 3934,3833, 3631, 3732, 4338, 4540, 4439, or 4237 is monoclonal antibody 2218,2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 3934,3833, 3631, 3732, 4338, 4540, 4439, or 4237.

In an embodiment, the antibody molecule is a humanized monoclonalantibody 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210,2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525,3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540,4540-063, 4540-033, 4439, or 4237. In an embodiment, the antibodymolecule comprises a heavy chain variable region (VH) having an aminoacid sequence described in Table 1 or 5. In an embodiment, the antibodymolecule comprises a light chain variable region (VL) having an aminoacid sequence described in Table 1 or 5. In antibody molecule comprisesa heavy chain variable region (VH) having an amino acid sequencedescribed in Table 1 or 5 and a light chain variable region (VL) havingan amino acid sequence described in Table 1 or 5.

In an embodiment, the antibody molecule competes for binding to humanAPRIL, mouse APRIL, or both. In an embodiment, the antibody moleculebinds, or substantially binds, to human APRIL at an EC₅₀ of 20 nM orless, e.g., 10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM orless, 0.005 nM or less, 0.002 nM or less, or 0.001 nM or less, e.g.,between 0.001 nM and 100 nM, e.g., between 0.001 nM and 50 nM, between0.01 nM and 20 nM, between 0.1 nM and 20 nM, e.g., between 0.1 nM and 10nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nM and0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nMor less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM orless, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nMor less, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM orless, 0.01 nM or less, 0.005 nM or less, 0.002 nM or less, or 0.001 nMor less, e.g., between 0.001 nM and 100 nM, e.g., between 0.001 nM and50 nM, between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, e.g.,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule does not bind, or binds to mouseAPRIL with low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000nM or more, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein.

In an embodiment, binding of the antibody molecule to APRIL (e.g., humanAPRIL) inhibits, or substantially inhibits, the binding of the CRD2domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL).

In an embodiment, binding of the antibody molecule to human APRILinhibits, or substantially inhibits, the binding of human TACI, to oneor more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues fromTable 3. In an embodiment, binding of the antibody molecule to humanAPRIL, inhibits, or substantially inhibits, the binding of human TACI toone or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the human APRILresidues from Table 4. In an embodiment, binding of the antibodymolecule to human APRIL, inhibits, or substantially inhibits, thebinding of human TACI to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or all of the human APRIL residues fromTable 7. In an embodiment, binding of the antibody molecule to humanAPRIL, inhibits, or substantially inhibits, the binding of human TACI toone or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residuesfrom Table 8.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both).

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), e.g., at an IC₅₀ of 200 nMor less, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less,30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less,7 nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2nM or less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM orless, 0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less,0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nMand 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein.

In an embodiment, the antibody molecule does not inhibit, or does notsubstantially inhibit, binding of APRIL (e.g., human APRIL, mouse APRIL,or both) to BCMA (e.g., human BCMA, mouse BCMA, or both).

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in any of Tables 3-4 or 7-8. In anembodiment, the antibody molecule binds, or substantially binds, to aconformational epitope.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in Table 3. In an embodiment, theantibody molecule binds to an epitope that comprises or consists of oneor more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRIL residues fromTable 3. In an embodiment, the antibody molecule binds, or substantiallybinds, to an epitope that comprises APRIL residues from two monomers,e.g., one or more residues from monomer A and monomer B as shown inTable 3.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, residueswithin a region of human APRIL as defined in Table 4. In an embodiment,the antibody molecule binds, or substantially binds, to an epitope thatcomprises consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, orall of the APRIL residues from Table 4. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that comprises oneor more APRIL residues from the C-D loop (e.g., the loop connectingβ-sheets C and D), the G-H loop (e.g., the loop connecting β-sheets Gand H), or both.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or all, residues within a region of human APRIL as defined inTable 7. In an embodiment, the antibody molecule binds, or substantiallybinds, to an epitope that comprises or consists of one or more, e.g., 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all, of thehuman APRIL residues from Table 7. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 7.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, residues within a regionof human APRIL as defined in Table 8. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that comprises orconsists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, of the humanAPRIL residues from Table 8. In an embodiment, the antibody moleculebinds, or substantially binds, to an epitope that overlaps an epitopethat comprises or consists of all of the human APRIL residues from Table8.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of humanAPRIL from positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7,8, 9, or all) residues of mouse APRIL from positions 96-105. In anembodiment, the antibody molecule does not bind, or does notsubstantially bind, to one, two or all of Asp129, Arg233, or His203 ofhuman APRIL.

In an embodiment, the antibody molecule is an IgG antibody molecule,e.g., comprising a heavy chain constant region of IgG, e.g., chosen fromIgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In anembodiment, the antibody molecule is an IgG1 antibody molecule. Inanother embodiment, the antibody molecule is an IgG2 antibody molecule.In an embodiment, the antibody molecule comprises a light chain constantregion of kappa or lambda light chain.

In an embodiment, the antibody molecule comprises an Fc region. In anembodiment, the Fc region comprises one or more mutations located at theinterface between the CH2 and CH3 domains (e.g., to increase the bindingaffinity to neonatal receptor FcRn and/or the half-life of the antibodymolecule). In an embodiment, the Fc region comprises one or moremutations, e.g., one or more (e.g., 2, 3, 4, 6 or all) mutations chosenfrom T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combinationthereof, of IgG1. In an embodiment, the Fc region comprises one or moremutations at positions 233-236 or 322 of human IgG1 or IgG2, or one ormore substitutions at positions 327, 330 or 331 of human IgG4 (e.g., toreduce complement-dependent cytotoxicity (CDC)). In an embodiment, theFc region comprises one or more (e.g., 2, 3, 4, 6 7 or all) mutationschosen from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, orany combination thereof.

In an embodiment, the antibody molecule is a humanized antibodymolecule, e.g., comprising one or more framework regions derived fromhuman framework germline sequence. In an embodiment, the antibodymolecule comprises two heavy chain variable regions and two light chainvariable regions. In an embodiment, the antibody molecule is a Fab,F(ab′)2, Fv, Fd, or a single chain Fv fragment (scFv).

In an aspect, the disclosure features an anti-APRIL antibody moleculedescribed herein, e.g., a synthetic or isolated anti-APRIL antibodymolecule described herein.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 2218 (e.g., SEQID NO: 1 or 7); an HCDR2 comprising an amino acid sequence that differsby no more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the HCDR2of monoclonal antibody 2218 (e.g., SEQ ID NO: 2 or 8); or an HCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 2218 (e.g., SEQ ID NO: 3), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 2218(e.g., SEQ ID NO: 4); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 2218 (e.g., SEQ ID NO: 5); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2218 (e.g., SEQ ID NO: 6).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 2218 (e.g., SEQ IDNO: 9); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2218 (e.g., SEQ ID NO: 10).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 71 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 72 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 2218. Inan embodiment, monoclonal antibody 2218 is humanized monoclonal antibody2218. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of any of SEQ ID NO: 190-201, a VL comprisingthe amino acid sequence of any of SEQ ID NO: 202-208, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule binds to human APRIL at an EC₅₀ of 1nM or less, e.g., about 0.6 nM. In an embodiment, the antibody moleculedoes not bind to mouse APRIL, or binds to mouse APRIL with low affinity,e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM or more, e.g., asdetermined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human TACI at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein. In an embodiment, theantibody molecule inhibits binding of human APRIL to human TACI at anIC₅₀ of 1 nM or less, e.g., about 0.74 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 0.5 nM or less, e.g.,about 0.22 nM.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence of G-Y-T-F-T-D-Y (SEQ ID NO: 11); an HCDR2comprising an amino acid sequence of Y-P-L-R-G-S(SEQ ID NO: 12); or anHCCDR3 comprising an amino acid sequence of H-G-A-Y-Y-S-N-A-F-D-Y (SEQID NO: 13), or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence of X1-X2-S-X4-S-V-D-N-D-G-I-R-F-X14-H (SEQ ID NO:327), wherein X1 is R or K; X2 is A or S; X4 is E or Q; and X14 is M orL; an LCDR2 comprising an amino acid sequence of R-A-S-X4-X5-X6-X7 (SEQID NO: 328), wherein X4 is N or T; X5 is L or R; X6 is E or A; and X7 isS or T; or an LCDR3 comprising an amino acid sequence ofQ-Q-S-N-K-D-P-Y-T (SEQ ID NO: 16).

In another embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence of D-Y-T-I-H (SEQ ID NO: 17); an HCDR2 comprising anamino acid sequence of W-I-Y-P-L-R-G-S-I-N-Y-X12-X13-X14-F-X16-X17 (SEQID NO: 329), wherein X12 is N, S, or A, X13 is E, P, or Q; X14 is K orS; X16 is K or Q; and X17 is D or G; or an HCCDR3 comprising an aminoacid sequence of H-G-A-Y-Y-S-N-A-F-D-Y (SEQ ID NO: 13), or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence of X1-X2-S-X4-S-V-D-N-D-G-I-R-F-X14-H (SEQ ID NO:327), wherein X1 is R or K; X2 is A or S; X4 is E or Q; and X14 is M orL; an LCDR2 comprising an amino acid sequence of R-A-S-X4-X5-X6-X7 (SEQID NO: 328), wherein X4 is N or T; X5 is L or R; X6 is E or A; and X7 isS or T; or an LCDR3 comprising an amino acid sequence ofQ-Q-S-N-K-D-P-Y-T (SEQ ID NO: 16).

In an embodiment, the antibody molecule is any of antibodies 2419,2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306,2419-1310, or 2419-1406.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 0.01 nM or less, e.g., about0.001-0.005 nM or 0.002-0.004 nM, e.g., about 0.001, 0.002, 0.003,0.004, or 0.005 nM. In an embodiment, the antibody molecule does notbind to mouse APRIL, or binds to mouse APRIL with low affinity, e.g., atan EC₅₀ of 1000 nM or more, e.g., 2000 nM or more, e.g., as determinedby a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human TACI at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein. In an embodiment, theantibody molecule inhibits binding of human APRIL to human TACI at anIC₅₀ of 0.5 nM or less, e.g., about 0.1-0.5 nM or 0.2-0.4 nM, e.g.,about 0.1, 0.2, 0.3, 0.4, or 0.5 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 0.5 nM or less, e.g.,about 0.1-0.5 nM or 0.2-0.4 nM, e.g., about 0.1, 0.2, 0.3, 0.4, or 0.5nM.

In another embodiment, the antibody molecule comprises (i) a heavy chainvariable region (VH), wherein the heavy chain variable region comprisesthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: an HCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR1 of monoclonal antibody 2419 (e.g., SEQ ID NO: 11 or 17); anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2419 (e.g., SEQ ID NO: 12 or 18); or an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2419 (e.g., SEQID NO: 13), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 2419(e.g., SEQ ID NO: 14); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 2419 (e.g., SEQ ID NO: 15); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2419 (e.g., SEQ ID NO: 16).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 2419 (e.g., SEQ IDNO: 19); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2419 (e.g., SEQ ID NO: 20).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 73 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 74 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 2419. Inan embodiment, monoclonal antibody 2419 is humanized monoclonal antibody2419. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of any of SEQ ID NOS: 209-214, a VL comprisingthe amino acid sequence of any of SEQ ID NOS: 215-219, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 1 nM or less, e.g., about0.8 nM, about 0.003 nM, or about 0.002 nM. In an embodiment, theantibody molecule does not bind, or bind to mouse APRIL with lowaffinity, e.g., at an EC₅₀ of 500 nM or more.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human TACI, at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein. In an embodiment, theantibody molecule inhibits binding of human APRIL to human TACI at anIC₅₀ of 1 nM or less, e.g., about 0.74 nM, about 0.4 nM, 0.3 nM, or 0.2nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 4 nM, about 2 nM, or about 1 nM, or 0.5 nM or less, e.g., about0.22 nM, about 1 nM, about 0.7 nM, about 0.3 nM, about 0.2 nM, or about0.1 nM.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of a 2419-related antibody (e.g., SEQID NO: 11 or 17); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of the 2419-related antibody (e.g., SEQ ID NOS: 12, 282, 287,or 290); or an HCDR3 comprising an amino acid sequence that differs byno more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the HCDR3of the 2419-related antibody (e.g., SEQ ID NO: 13), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of the 2419-related antibody(e.g., SEQ ID NOS: 280 or 314); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of the 2419-related antibody (e.g., SEQ IDNOS: 281, 285, 293, or 315); or an LCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR3 of the 2419-related antibody (e.g., SEQ IDNO: 16).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of the 2419-related antibody (e.g., SEQ IDNOS: 283, 288, 289, 291, 292, 294, 296, or 317); or (ii) a VL comprisingan amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has atleast 85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of the VL of the 2419-related antibody (e.g., SEQ ID NOS: 284,286, 295, or 316).

In an embodiment, the antibody molecule comprises a VH encoded by the VHnucleotide sequence of the 2419-related antibody (e.g., SEQ ID NOS: 304,307, 308, 309, 310, 311, 313, or 319) (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the VL nucleotidesequence of the 2419-related antibody (e.g., SEQ ID NOS: 305, 306, 312,or 318) (or a nucleotide sequence substantially identical thereto), orboth.

In an embodiment, the 2419-related antibody molecule is chosen fromantibodies 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605,2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305,2419-1306, 2419-1310, or 2419-1406. In an embodiment, the 2419-relatedantibody is humanized antibody molecule. In an embodiment, the antibodymolecule comprises a VH comprising the amino acid sequence of any of SEQID NOS: 209-214, 283, 288, 289, 291, 292, 294, 296, or 317, a VLcomprising the amino acid sequence of any of SEQ ID NOS: 215-219, 284,286, 295, or 316, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less or less, 8 nM or less, 7 nM or less, 6 nM orless, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM orless, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less,0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005nM or less, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001nM and 20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,e.g., between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nMand 5 nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM,between 0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between0.01 nM and 0.1 nM, e.g., as determined by a method described herein. Inan embodiment, the antibody molecule binds to human APRIL at an EC₅₀ of1 nM or less, e.g., about 0.8 nM, about 0.003 nM, or about 0.002 nM.

In an embodiment, the antibody molecule does not bind, or bind to mouseAPRIL with low affinity, e.g., at an EC₅₀ of 500 nM or more.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 1 nM or less, e.g.,about 0.74 nM, about 0.4 nM, 0.3 nM, or 0.2 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 4 nM, about 2 nM, or about 1 nM, or 0.5 nM or less, e.g., about0.22 nM, about 1 nM, about 0.7 nM, about 0.3 nM, about 0.2 nM, or about0.1 nM.

In another embodiment, the antibody molecule comprises (i) a heavy chainvariable region (VH), wherein the heavy chain variable region comprisesthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: an HCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR1 of monoclonal antibody 2922 (e.g., SEQ ID NO: 21 or 37); anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 2922 (e.g., SEQ ID NO: 32 or 38); or an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 2922 (e.g., SEQID NO: 33), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 2922(e.g., SEQ ID NO: 34); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 2922 (e.g., SEQ ID NO: 35); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2922 (e.g., SEQ ID NO: 36).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 2922 (e.g., SEQ IDNO: 39); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2922 (e.g., SEQ ID NO: 40).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 77 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 78 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 2922. Inan embodiment, the antibody molecule is humanized monoclonal antibody2922.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule binds to human APRIL at an EC₅₀ of 5nM or less, e.g., about 3.3 nM. In an embodiment, the antibody moleculedoes not bind, or binds to mouse APRIL with low affinity, e.g., at anEC₅₀ of 1000 nM or more, e.g., 2000 nM or more, e.g., as determined by amethod described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 50 nM or less, e.g.,about 31.64 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the IC₅₀ is 50 nM or less. In anembodiment, the antibody molecule inhibits binding of human TACI tohuman BCMA at an IC₅₀ of 25 nM or less, e.g., about 21.96 nM.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3327 (e.g., SEQID NO: 51 or 57); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 52 or 58); or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3327 (e.g., SEQ ID NO: 53), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3327(e.g., SEQ ID NO: 54); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3327 (e.g., SEQ ID NO: 55); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3327 (e.g., SEQ ID NO: 56).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3327 (e.g., SEQ IDNO: 59); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3327 (e.g., SEQ ID NO: 60).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 81 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 82 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3327. Inan embodiment, the antibody molecule is humanized antibody 3327.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 100 nM or less, e.g.,80 nM or less, 60 nM or less, 40 nM or less, 20 nM or less, 10 nM orless, 9 nM or less 9 nM or less, 8 nM or less, 7 nM or less, 6 nM orless, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM orless, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less,0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005nM or less, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001nM and 100 nM, e.g., between 0.001 nM and 50 nM, between 0.01 nM and 20nM, between 0.1 nM and 10 nM, between 0.5 nM and 5 nM or between 1 nMand 5 nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM,between 0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between0.01 nM and 0.1 nM, e.g., as determined by a method described herein. Inan embodiment, the antibody molecule does not bind, or binds to mouseAPRIL with low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000nM or more, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 3.16 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the IC₅₀ is 50 nM or less. In anembodiment, the antibody molecule inhibits binding of human APRIL tohuman BCMA at an IC₅₀ of 5 nM or less, e.g., about 2.35 nM.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4035 (e.g., SEQID NO: 93 or 99); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO: 94 or 100); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4035 (e.g., SEQ ID NO: 95), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 4035(e.g., SEQ ID NO: 96); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 4035 (e.g., SEQ ID NO: 97); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4035 (e.g., SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4035 (e.g., SEQ IDNO: 101); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4035 (e.g., SEQ ID NO: 102).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 173 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 174 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4035. Inan embodiment, monoclonal antibody 4035 is humanized monoclonal antibody4035. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of any of SEQ ID NO: 220-227 or 262-265, a VLcomprising the amino acid sequence of any of SEQ ID NO: 228-234, orboth.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule binds to human APRIL at an EC₅₀ of0.01 nM or less, e.g., about 0.001-0.002 nM. In an embodiment, theantibody molecule does not bind, or binds to mouse APRIL with lowaffinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM or more,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 3.16 nM, or about 0.1-0.5 nM or 0.2-0.4 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 2.35 nM, or about 0.1-0.5 nM or 0.1-0.2 nM.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4035-062 (e.g.,SEQ ID NO: 93 or 99); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 94 or 273);or an HCDR3 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4035-062 (e.g., SEQ ID NO: 95), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody4035-062 (e.g., SEQ ID NO: 96); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4035-062 (e.g., SEQ IDNO: 97); or an LCDR3 comprising an amino acid sequence that differs byno more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the LCDR3of monoclonal antibody 4035-062 (e.g., SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4035-062 (e.g., SEQID NO: 225); or (ii) a VL comprising an amino acid sequence that differsby no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15amino acid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or100% homology with, the amino acid sequence of the VL of monoclonalantibody 4035-062 (e.g., SEQ ID NO: 229).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 299 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 300 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4035-062.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule binds to human APRIL at an EC₅₀ of0.01 nM or less, e.g., about 0.001-0.002 nM. In an embodiment, theantibody molecule does not bind, or binds to mouse APRIL with lowaffinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM or more,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 1 nM or less, e.g.,about 0.1-0.5 nM or 0.2-0.4 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.1-0.5 nM or 0.1-0.2 nM.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising theamino acid sequence of I-Y-D-V-H (SEQ ID NO: 99); an HCDR2 comprisingthe amino acid sequence of V-I-W-S-D-G-S-T-D-Y-N-X12-X13-X14-X15-S(SEQID NO: 342), X12 is A or P, X13 is A or S, X14 is F or L, and X15 is Ior K; or an HCDR3 comprising the amino acid sequence ofN-W-V-D-Q-A-W-F-A-Y (SEQ ID NO: 95), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingthe amino acid sequence of R-A-S-K-N-I-Y-S-Y-L-A (SEQ ID NO: 96); anLCDR2 comprising the amino acid sequence of N-A-K-T-L-P-E (SEQ ID NO:97); or an LCDR3 comprising the amino acid sequence of Q-H-H-Y-G-T-P-L-T(SEQ ID NO: 98).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of SEQ ID NO: 101 or 225; or (ii) a VL comprising anamino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 amino acid residues from, or has at least85, 90, 95, 96, 97, 98, 99, or 100% homology with, the amino acidsequence of SEQ ID NO: 102 or 229.

In an embodiment, the antibody molecule is monoclonal antibody 4035. Inan embodiment, the antibody molecule is monoclonal antibody 4035-062.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3934 (e.g., SEQID NO: 103 or 109); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 104 or 110); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3934 (e.g., SEQ ID NO: 105), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3934(e.g., SEQ ID NO: 106); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3934 (e.g., SEQ ID NO: 107); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3934 (e.g., SEQ ID NO: 108).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3934 (e.g., SEQ IDNO: 111); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3934 (e.g., SEQ ID NO: 112).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 175 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 176 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3934. Inan embodiment, the antibody molecule is humanized monoclonal antibody3934.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule does not bind, or binds to mouse APRILwith low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM ormore, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 3.16 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 2.35 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4338 (e.g., SEQID NO: 11 or 149); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO: 142 or 150); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4338 (e.g., SEQ ID NO: 143), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 4338(e.g., SEQ ID NO: 144 or 146); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4338 (e.g., SEQ ID NO:107 or 147); or an LCDR3 comprising an amino acid sequence that differsby no more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the LCDR3of monoclonal antibody 4338 (e.g., SEQ ID NO: 145 or 148).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4338 (e.g., SEQ IDNO: 151); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4338 (e.g., SEQ ID NO: 152 or 153).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 183 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 184 or 185 (or a nucleotide sequencesubstantially identical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4338. Inan embodiment, the antibody molecule is humanized monoclonal antibody4338.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule does not bind, or binds to mouse APRILwith low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM ormore, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 3.16 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 2.35 nM.

In another embodiment, the antibody molecule comprises (i) a heavy chainvariable region (VH), wherein the heavy chain variable region comprisesthree heavy chain complementarity determining regions (HCDR1, HCDR2, andHCDR3), wherein the heavy chain variable region comprises one, two, orall of the following: an HCDR1 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR1 of monoclonal antibody 4237 (e.g., SEQ ID NO: 163 or 169); anHCDR2 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR2 of monoclonalantibody 4237 (e.g., SEQ ID NO: 164 or 170); or an HCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR3 of monoclonal antibody 4237 (e.g., SEQID NO: 165), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 4237(e.g., SEQ ID NO: 166); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 4237 (e.g., SEQ ID NO: 167); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4237 (e.g., SEQ ID NO: 168).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4237 (e.g., SEQ IDNO: 171); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4237 (e.g., SEQ ID NO: 172).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 188 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 189 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4237. Inan embodiment, monoclonal antibody 4237 is humanized monoclonal antibody4237. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of any of SEQ ID NO: 235-240, a VL comprisingthe amino acid sequence of any of SEQ ID NO: 241-245, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule does not bind, or binds to mouse APRILwith low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM ormore, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 3.16 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 5 nM or less, e.g.,about 2.35 nM.

In another embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence of G-Y-X3-X4-T-X6-X7-Y (SEQ ID NO: 330), wherein X3is S or T; X4 is I or F; X6 is S or absent; and X7 is G, D or S; anHCDR2 comprising an amino acid sequence of X3-X4-X5-X6-X7-X8 (SEQ ID NO:331), wherein X3 is absent, N or Y; X4 is S or P, X5 is Y, L or R; X6 isD, N or R; X7 is G or S; and X8 is Y, D or S; or an HCCDR3 comprising anamino acid sequence of X1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO:332), wherein X1 is Y, E or H; X2 is absent or G; X3 is Y, D or A; X4 isD, G or Y; X6 is E, absent or D; X7 is D, Y, S or K; X8 is W, N or R; X9is Y, A or G; X11 is G or D; and X12 is V or Y, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence of X1-A-S-X4-S-V-X7-X8-X9-G-X11-X12-X13-X14-X15(SEQ ID NO: 333), wherein X1 is R or K; X4 is E or Q; X7 is D or S; X8is N, F, I or N; X9 is Y, A, I or D; X11 is I or T; X12 is S, N or R;X13 is F, L or S; X14 is M or I; and X15 is N or H; an LCDR2 comprisingan amino acid sequence of X1-A-S-N-X5-X6-X7 (SEQ ID NO: 334), wherein X1is A, R or H; X5 is Q or L; X6 is G or E; and X7 is S, P or T; or anLCDR3 comprising an amino acid sequence of X1-Q-S-X4-X5-X6-P-X8-T (SEQID NO: 335), wherein X1 is Q or L; X4 is K, R or N; X5 is E or K; X6 isV, Y, I or D; and X8 is R, W or Y.

In an embodiment, the antibody molecule is any of monoclonal antibodies2218, 2419, 2922, or 3327.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule does not bind, or binds to mouse APRILwith low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM ormore, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, or 0.1 nM or less, e.g., between 0.1 and 50 nM, e.g.,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.5 nM and 5nM, or between 1 nM and 5 nM, e.g., as determined by a method describedherein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein.

In another embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence of X6-X7-Y-X9-X10-X11 (SEQ ID NO: 336), wherein X6is S or absent; X7 is G, D or S; X9 is Y, F, T or D; X10 is W, M, I orV; and X11 is N, H or F; an HCDR2 comprising an amino acid sequence ofX1-I-X3-X4-X5-X6-X7-X8-X9-X10-Y-N-X13-X14-X15-K-X17 (SEQ ID NO: 337),wherein X1 is Y, R or W; X3 is absent, N or Y; X4 is S or P, X5 is Y, Lor R; X6 is D, N or R; X7 is G or S; X8 is Y, D or S; X9 is N, T or I;X10 is N, F or K; X13 is P, Q or E; X14 is S or K; X15 is L or F; andX17 is N, G or D; or an HCCDR3 comprising an amino acid sequence ofX1-X2-X3-X4-Y-X6-X7-X8-X9-F-X11-X12 (SEQ ID NO: 332), wherein X1 is Y, Eor H; X2 is absent or G; X3 is Y, D or A; X4 is D, G or Y; X6 is E,absent or D; X7 is D, Y, S or K; X8 is W, N or R; X9 is Y, A or G; X11is G or D; and X12 is V or Y, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence of X1-A-S-X4-S-V-X7-X8-X9-G-X11-X12-X13-X14-X15(SEQ ID NO: 333), wherein X1 is R or K; X4 is E or Q; X7 is D or S; X8is N, F, I or N; X9 is Y, A, I or D; X11 is I or T; X12 is S, N or R;X13 is F, L or S; X14 is M or I; and X15 is N or H; an LCDR2 comprisingan amino acid sequence of X1-A-S-N-X5-X6-X7 (SEQ ID NO: 334), wherein X1is A, R or H; X5 is Q or L; X6 is G or E; and X7 is S, P or T; or anLCDR3 comprising an amino acid sequence of X1-Q-S-X4-X5-X6-P-X8-T (SEQID NO: 335), wherein X1 is Q or L; X4 is K, R or N; X5 is E or K; X6 isV, Y, I or D; and X8 is R, W or Y.

In an embodiment, the antibody molecule is any of monoclonal antibodies2218, 2419, 2922, or 3327. In an embodiment, the antibody molecule is ahumanized monoclonal antibody 2218, 2419, 2922, or 3327.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule does not bind, or binds to mouse APRILwith low affinity, e.g., at an EC₅₀ of 1000 nM or more, e.g., 2000 nM ormore, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of human APRIL tohuman TACI, at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nM orless, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM orless, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of human APRIL to human BCMA, at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein.

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3530 (e.g., SEQID NO: 61 or 64); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 62 or 65); or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3530 (e.g., SEQ ID NO: 63), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3530(e.g., SEQ ID NO: 67); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3530 (e.g., SEQ ID NO: 45); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3530 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3530 (e.g., SEQ IDNO: 66); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3530 (e.g., SEQ ID NO: 70).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 83 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 84 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3530. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3530.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 5 nM or less, e.g., about2.7 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of APRIL (e.g.,human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouseTACI, or both), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nMor less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 4.95 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.68 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3525 (e.g., SEQID NO: 61 or 64); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 62 or 65); or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3525 (e.g., SEQ ID NO: 63), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3525(e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3525 (e.g., SEQ ID NO: 45); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3525 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3525 (e.g., SEQ IDNO: 66); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3525 (e.g., SEQ ID NO: 50).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 83 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 80 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3525. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3525.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 5 nM or less, e.g., about2.5 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of APRIL (e.g.,human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouseTACI, or both), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nMor less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 4.05 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.85 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3833 (e.g., SEQID NO: 113 or 119); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 114 or 120); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3833 (e.g., SEQ ID NO: 115), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3833(e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3833 (e.g., SEQ ID NO: 117); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3833 (e.g., SEQ ID NO: 118).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3833 (e.g., SEQ IDNO: 121); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3833 (e.g., SEQ ID NO: 122).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 177 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 178 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3833. Inan embodiment, monoclonal antibody 3833 is a humanized monoclonalantibody 3833. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 246-250, a VLcomprising the amino acid sequence of any of SEQ ID NO: 251-253, orboth.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 5 nM or less, e.g., about2.5 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of APRIL (e.g.,human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouseTACI, or both), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nMor less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 4.05 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.85 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3631 (e.g., SEQID NO: 123 or 129); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 124 or 130); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3631 (e.g., SEQ ID NO: 125), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3631(e.g., SEQ ID NO: 126); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3631 (e.g., SEQ ID NO: 127); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3631 (e.g., SEQ ID NO: 128).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3631 (e.g., SEQ IDNO: 131); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3631 (e.g., SEQ ID NO: 132).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 179 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 180 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3631. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3631.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 5 nM or less, e.g., about2.5 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both. In an embodiment, the antibodymolecule inhibits, or substantially inhibits, binding of APRIL (e.g.,human APRIL, mouse APRIL, or both) to TACI (e.g., human TACI, mouseTACI, or both), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30 nMor less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nMor less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM orless, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less, 0.2nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or 0.01 nMor less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human TACI at an IC₅₀ of 5 nM or less, e.g.,about 4.05 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.85 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3732 (e.g., SEQID NO: 133 or 138); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 134 or 139); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3732 (e.g., SEQ ID NO: 135), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3732(e.g., SEQ ID NO: 136); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3732 (e.g., SEQ ID NO: 127); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3732 (e.g., SEQ ID NO: 137).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3732 (e.g., SEQ IDNO: 140); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3732 (e.g., SEQ ID NO: 141).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 181 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 182 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3732. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3732.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 5 nM or less, e.g., about2.5 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less 9 nMor less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 100 nM, e.g.,between 0.001 nM and 50 nM, between 0.01 nM and 20 nM, between 0.1 nMand 10 nM, between 0.5 nM and 5 nM or between 1 nM and 5 nM, between0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM,e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein. In an embodiment, theantibody molecule inhibits binding of human APRIL to human TACI at anIC₅₀ of 5 nM or less, e.g., about 4.05 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.85 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4540 (e.g., SEQID NO: 154 or 159); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 155 or 160); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4540 (e.g., SEQ ID NO: 156), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 4540(e.g., SEQ ID NO: 116); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 4540 (e.g., SEQ ID NO: 157); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4540 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4540 (e.g., SEQ IDNO: 161); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4540 (e.g., SEQ ID NO: 162).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 186 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 187 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4540. Inan embodiment, monoclonal antibody 4540 is a humanized monoclonalantibody 4540. In an embodiment, the antibody molecule comprises a VHcomprising the amino acid sequence of any of SEQ ID NO: 254-258, a VLcomprising the amino acid sequence of any of SEQ ID NO: 259-261, orboth.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4540-063 (e.g.,SEQ ID NO: 154 or 276); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 155 or 277);or an HCDR3 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4540-063 (e.g., SEQ ID NO: 156), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody4540-063 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540-063 (e.g., SEQ IDNO: 275); or an LCDR3 comprising an amino acid sequence that differs byno more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the LCDR3of monoclonal antibody 4540-063 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4540-063 (e.g., SEQID NO: 258); or (ii) a VL comprising an amino acid sequence that differsby no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15amino acid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or100% homology with, the amino acid sequence of the VL of monoclonalantibody 4540-063 (e.g., SEQ ID NO: 261).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 301 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 302 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4540-063.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4540-033 (e.g.,SEQ ID NO: 154 or 159); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 155 or 278);or an HCDR3 comprising an amino acid sequence that differs by no morethan 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99or 100% homology with, the amino acid sequence of the HCDR3 ofmonoclonal antibody 4540-033 (e.g., SEQ ID NO: 156), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody4540-033 (e.g., SEQ ID NO: 274); an LCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of the LCDR2 of monoclonal antibody 4540-033 (e.g., SEQ IDNO: 275); or an LCDR3 comprising an amino acid sequence that differs byno more than 1, 2, or 3 amino acid residues from, or has at least 85,90, 95, 99 or 100% homology with, the amino acid sequence of the LCDR3of monoclonal antibody 4540-033 (e.g., SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4540-033 (e.g., SEQID NO: 256); or (ii) a VL comprising an amino acid sequence that differsby no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15amino acid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or100% homology with, the amino acid sequence of the VL of monoclonalantibody 4540-033 (e.g., SEQ ID NO: 261).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 303 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 302 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4540-033.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all ofthe following: an HCDR1 comprising the amino acid sequence ofD-Y-Y-X4-N(SEQ ID NO: 343), where X4 is I or M; an HCDR2 comprising theamino acid sequence of W-I-F-P-G-S-G-S-T-Y-Y-X12-X13-K-X15-X16-G, whereX12 is N or A, X13 is E or Q, X15 is F or L, and X16 is K or Q (SEQ IDNO: 344); or an HCDR3 comprising the amino acid sequence ofG-D-S-G-R-A-M-D-Y (SEQ ID NO: 156), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, orall of the following: an LCDR1 comprising the amino acid sequence ofX1-A-S-Q-D-I-N-K-Y-I-A, wherein X1 is K or Q (SEQ ID NO: 345); an LCDR2comprising the amino acid sequence of Y-T-S-T-L-X6-X7, wherein X6 is Qor E, and X7 is S or T (SEQ ID NO: 346); or an LCDR3 comprising theamino acid sequence of L-Q-Y-D-N-L-L-T (SEQ ID NO: 158).

In another embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all ofthe following: an HCDR1 comprising the amino acid sequence ofG-Y-T-F-A-D-Y (SEQ ID NO: 154); an HCDR2 comprising the amino acidsequence of F-P-G-S-G-S (SEQ ID NO: 155); or an HCDR3 comprising theamino acid sequence of G-D-S-G-R-A-M-D-Y (SEQ ID NO: 156), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, orall of the following: an LCDR1 comprising the amino acid sequence ofX1-A-S-Q-D-I-N-K-Y-I-A, wherein X1 is K or Q (SEQ ID NO: 345); an LCDR2comprising the amino acid sequence of Y-T-S-T-L-X6-X7 (SEQ ID NO: 346),wherein X6 is Q or E, and X7 is S or T; or an LCDR3 comprising the aminoacid sequence of L-Q-Y-D-N-L-L-T (SEQ ID NO: 158).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of SEQ ID NOS: 161, 256 or 258; or (ii) a VLcomprising an amino acid sequence that differs by no more than 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from, orhas at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of SEQ ID NO: 162 or 261.

In an embodiment, the antibody molecule is monoclonal antibody 4540. Inanother embodiment, the antibody molecule is monoclonal antibody4540-063. In yet another embodiment, the antibody molecule is monoclonalantibody 4540-033.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL, mouse APRIL, or both.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, or 0.1 nM or less, e.g.,between 0.1 nM and 20 nM, e.g., between 0.1 nM and 10 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule binds to humanAPRIL at an EC₅₀ of 5 nM or less, e.g., about 2.5 nM.

In an embodiment, the antibody molecule binds, or substantially binds,to mouse APRIL at an EC₅₀ of 100 nM or less, e.g., 80 nM or less, 60 nMor less, 40 nM or less, 20 nM or less, 10 nM or less, 9 nM or less orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, or 0.1 nM or less, e.g.,between 0.1 nM and 20 nM, e.g., between 0.1 nM and 10 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI), BCMA (e.g., human BCMA), or both.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both), at an IC₅₀ of 50 nM orless, e.g., 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less,0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nMor less, 0.02 nM or less, or 0.01 nM or less, e.g., between 0.01 nM and50 nM, between 0.1 nM and 50 nM, between 0.1 nM and 25 nM, between 0.1nM and 10 nM, between 0.1 nM and 5 nM, between 0.1 nM and 1 nM, between0.1 nM and 0.5 nM, between 0.5 nM and 5 nM, or between 1 nM and 5 nM,e.g., as determined by a method described herein. In an embodiment, theantibody molecule inhibits binding of human APRIL to human TACI at anIC₅₀ of 5 nM or less, e.g., about 4.05 nM.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toBCMA (e.g., human BCMA, mouse BCMA, or both), at an IC₅₀ of 200 nM orless, 150 nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, 0.01nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50 nM,between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nM and 5nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between 0.5 nMand 5 nM, or between 1 nM and 5 nM, e.g., as determined by a methoddescribed herein. In an embodiment, the antibody molecule inhibitsbinding of human APRIL to human BCMA at an IC₅₀ of 1 nM or less, e.g.,about 0.85 nM.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 2621 (e.g., SEQID NO: 21 or 27); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 22 or 28); or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 2621 (e.g., SEQ ID NO: 23), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 2621(e.g., SEQ ID NO: 24); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 2621 (e.g., SEQ ID NO: 25); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 2621 (e.g., SEQ ID NO: 26).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 2621 (e.g., SEQ IDNO: 29); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody2621 (e.g., SEQ ID NO: 30).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 75 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 76 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 2621. Inan embodiment, the antibody molecule is a humanized monoclonal antibody2621.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL at an EC₅₀ of 20 nM or less, e.g., 10 nM or less, 9 nM orless, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4 nM orless, 3 nM or less, 2 nM or less, 1 nM or less, 0.8 nM or less, 0.6 nMor less, 0.4 nM or less, 0.2 nM or less, 0.1 nM or less, 0.05 nM orless, 0.02 nM or less, 0.01 nM or less, 0.005 nM or less, 0.002 nM orless, or 0.001 nM or less, e.g., between 0.001 nM and 20 nM, e.g.,between 0.01 nM and 20 nM, between 0.1 nM and 20 nM, between 0.1 nM and10 nM, between 0.5 nM and 5 nM, between 1 nM and 5 nM, between 0.001 nMand 0.1 nM, between 0.001 nM and 0.01 nM, between 0.001 nM and 0.005 nM,between 0.01 nM and 0.05 nM, or between 0.01 nM and 0.1 nM, e.g., asdetermined by a method described herein. In an embodiment, the antibodymolecule binds to human APRIL at an EC₅₀ of 1 nM or less, e.g., about0.7 nM. In an embodiment, the antibody molecule does not bind, or bindsto mouse APRIL with low affinity, e.g., at an EC₅₀ of 1000 nM or more,e.g., 2000 nM or more, e.g., as determined by a method described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI). In an embodiment, the antibody molecule inhibits, orsubstantially inhibits, binding of APRIL (e.g., human APRIL) to TACI(e.g., human TACI), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nMand 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein. In an embodiment, the antibody moleculeinhibits binding of human APRIL to human TACI at an IC₅₀ of about 1 nMor less.

In an embodiment, the antibody molecule does not inhibit, or does notsubstantially inhibit, binding of APRIL (e.g., human APRIL) to BCMA(e.g., human BCMA).

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 3125 (e.g., SEQID NO: 11 or 47); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 42 or 48); or anHCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 3125 (e.g., SEQ ID NO: 43), and

(ii) a light chain variable region (VH), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 3125(e.g., SEQ ID NO: 44); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 3125 (e.g., SEQ ID NO: 45); or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 3125 (e.g., SEQ ID NO: 46).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 3125 (e.g., SEQ IDNO: 49); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody3125 (e.g., SEQ ID NO: 50).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 79 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 80 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 3125. Inan embodiment, the antibody molecule is a humanized monoclonal antibody3125.

In an embodiment, the antibody molecule binds, or substantially binds,to human APRIL. In an embodiment, the antibody molecule binds, orsubstantially binds, to human APRIL at an EC₅₀ of 20 nM or less, e.g.,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.8nM or less, 0.6 nM or less, 0.4 nM or less, 0.2 nM or less, 0.1 nM orless, 0.05 nM or less, 0.02 nM or less, 0.01 nM or less, 0.005 nM orless, 0.002 nM or less, or 0.001 nM or less, e.g., between 0.001 nM and20 nM, e.g., between 0.01 nM and 20 nM, between 0.1 nM and 20 nM,between 0.1 nM and 10 nM, between 0.5 nM and 5 nM, between 1 nM and 5nM, between 0.001 nM and 0.1 nM, between 0.001 nM and 0.01 nM, between0.001 nM and 0.005 nM, between 0.01 nM and 0.05 nM, or between 0.01 nMand 0.1 nM, e.g., as determined by a method described herein. In anembodiment, the antibody molecule binds to human APRIL at an EC₅₀ of 20nM or less, e.g., about 13 nM. In an embodiment, the antibody moleculedoes not bind, or binds to mouse APRIL with low affinity, e.g., at anEC₅₀ of 1000 nM or more, e.g., 2000 nM or more, e.g., as determined by amethod described herein.

In an embodiment, the antibody molecule inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL) to TACI (e.g., humanTACI). In an embodiment, the antibody molecule inhibits, orsubstantially inhibits, binding of APRIL (e.g., human APRIL) to TACI(e.g., human TACI), at an IC₅₀ of 50 nM or less, e.g., 40 nM or less, 30nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7nM or less, 6 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nMor less, 1 nM or less, 0.8 nM or less, 0.6 nM or less, 0.4 nM or less,0.2 nM or less, 0.1 nM or less, 0.05 nM or less, 0.02 nM or less, or0.01 nM or less, e.g., between 0.01 nM and 50 nM, between 0.1 nM and 50nM, between 0.1 nM and 25 nM, between 0.1 nM and 10 nM, between 0.1 nMand 5 nM, between 0.1 nM and 1 nM, between 0.1 nM and 0.5 nM, between0.5 nM and 5 nM, or between 1 nM and 5 nM, e.g., as determined by amethod described herein. In an embodiment, the antibody moleculeinhibits binding of human APRIL to human TACI at an IC₅₀ of 150 nM orless, e.g., about 112.97 nM. In an embodiment, the antibody moleculedoes not inhibit, or does not substantially inhibit, binding of APRIL(e.g., human APRIL) to BCMA (e.g., human BCMA).

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the HCDR1 of monoclonal antibody 4439 (e.g., SEQID NO: 266 or 269); an HCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe HCDR2 of monoclonal antibody 4439 (e.g., SEQ ID NO: 267 or 270); oran HCDR3 comprising an amino acid sequence that differs by no more than1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or100% homology with, the amino acid sequence of the HCDR3 of monoclonalantibody 4439 (e.g., SEQ ID NO: 268), and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of monoclonal antibody 4439(e.g., SEQ ID NO: 146); an LCDR2 comprising an amino acid sequence thatdiffers by no more than 1, 2, or 3 amino acid residues from, or has atleast 85, 90, 95, 99 or 100% homology with, the amino acid sequence ofthe LCDR2 of monoclonal antibody 4439 (e.g., SEQ ID NO: 147); or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the LCDR3 of monoclonalantibody 4439 (e.g., SEQ ID NO: 148).

In an embodiment, the antibody molecule comprises one or both of: (i) aVH comprising an amino acid sequence that differs by no more than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from,or has at least 85, 90, 95, 96, 97, 98, 99, or 100% homology with, theamino acid sequence of the VH of monoclonal antibody 4439 (e.g., SEQ IDNO: 271); or (ii) a VL comprising an amino acid sequence that differs byno more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 aminoacid residues from, or has at least 85, 90, 95, 96, 97, 98, 99, or 100%homology with, the amino acid sequence of the VL of monoclonal antibody4439 (e.g., SEQ ID NO: 272).

In an embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 297 (or a nucleotide sequencesubstantially identical thereto) or a VL encoded by the nucleotidesequence of SEQ ID NO: 298 (or a nucleotide sequence substantiallyidentical thereto), or both.

In an embodiment, the antibody molecule is monoclonal antibody 4439. Inan embodiment, monoclonal antibody 4439 is humanized monoclonal antibody4439.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in any of Tables 3-4 or 7-8.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in Table 3. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatcomprises or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, ofthe human APRIL residues from Table 3. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 3. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises APRIL residues fromtwo monomers, e.g., one or more residues from monomer A and monomer B asshown in Table 3.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, residueswithin a region of human APRIL as defined in Table 4. In an embodiment,the antibody molecule binds, or substantially binds, to an epitope thatcomprises or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,or all, of the human APRIL residues from Table 4. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatoverlaps an epitope that comprises or consists of all of the human APRILresidues from Table 4. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises one or more APRILresidues from the C-D loop (e.g., the loop connecting β-sheets C and D),the G-H loop (e.g., the loop connecting β-sheets G and H), or both.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or all, residues within a region of human APRIL as defined inTable 7. In an embodiment, the antibody molecule binds, or substantiallybinds, to an epitope that comprises or consists of one or more, e.g., 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all, of thehuman APRIL residues from Table 7. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 7.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within aregion of human APRIL as defined in Table 8. In an embodiment, theantibody molecule binds, or substantially binds, to an epitope thatcomprises or consists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all, ofthe human APRIL residues from Table 8. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 8. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises APRIL residues fromtwo monomers, e.g., one or more residues from monomer A and monomer B asshown in Table 8.

In an embodiment, the antibody molecule is an IgG antibody molecule,e.g., comprising a heavy chain constant region of IgG, e.g., chosen fromIgG1, IgG2 (e.g., IgG2a), IgG3, or IgG4, e.g., IgG2 or IgG4. In anembodiment, the antibody molecule is an IgG1 antibody molecule. Inanother embodiment, the antibody molecule is an IgG2 antibody molecule.In an embodiment, the antibody molecule comprises a light chain constantregion of kappa or lambda light chain.

In an embodiment, the antibody molecule comprises an Fc region. In anembodiment, the Fc region comprises one or more mutations located at theinterface between the CH2 and CH3 domains (e.g., to increase the bindingaffinity to neonatal receptor FcRn and/or the half-life of the antibodymolecule). In an embodiment, the Fc region comprises one or moremutations, e.g., one or more (e.g., 2, 3, 4, 6 or all) mutations chosenfrom T250Q, M252Y, S254T, T256E, M428L, H433K, N434F, or any combinationthereof, of IgG1. In an embodiment, the Fc region comprises one or moremutations at positions 233-236 or 322 of human IgG1 or IgG2, or one ormore substitutions at positions 327, 330 or 331 of human IgG4 (e.g., toreduce complement-dependent cytotoxicity (CDC)). In an embodiment, theFc region comprises one or more (e.g., 2, 3, 4, 6 7 or all) mutationschosen from E233P, L234V, L235A, G236, K322A, A327G, A330S, P331S, orany combination thereof.

In an embodiment, the antibody molecule is a humanized antibodymolecule, e.g., as described in Table 5, e.g., comprising one or moreframework regions derived from human framework germline sequence.

In an embodiment, the antibody molecule comprises two heavy chainvariable regions and two light chain variable regions. In an embodiment,the antibody molecule is a Fab, F(ab′)2, Fv, Fd, or a single chain Fvfragment (scFv).

In an aspect, the disclosure features a composition, e.g.,pharmaceutical composition, comprising an antibody molecule describedherein. In an embodiment, the composition further comprises apharmaceutical acceptable carrier.

In an aspect, the disclosure features a nucleic acid molecule encoding aheavy chain variable region (VH), a light chain variable region (VL), orboth, of an antibody molecule described herein.

In an aspect, the disclosure features a vector comprising a nucleic acidmolecule described herein.

In an aspect, the disclosure features a cell, e.g., an isolated cell,comprising a nucleic acid molecule described herein or a vectordescribed herein.

In an aspect, the disclosure features a kit comprising an antibodymolecule described herein and instructions to use of the antibodymolecule.

In an aspect, the disclosure features a container comprising an antibodymolecule described herein.

In an aspect, the disclosure features a method of producing ananti-APRIL antibody molecule, the method comprising culturing a celldescribed herein under conditions that allow production of an antibodymolecule, thereby producing the antibody molecule.

In an embodiment, the method further comprises isolating the antibodymolecule.

In an aspect, the disclosure features a method of treating IgAnephropathy, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating IgA nephropathy.

In an embodiment, the antibody molecule is administered to the subjectintravenously.

In an embodiment, the antibody molecule is administered to the subjectat a dose between 0.1 mg/kg and 50 mg/kg, e.g., between 0.2 mg/kg and 25mg/kg, between 0.5 mg/kg and 10 mg/kg, between 0.5 mg/kg and 5 mg/kg,between 0.5 mg/kg and 3 mg/kg, between 0.5 mg/kg and 2.5 mg/kg, between0.5 mg/kg and 2 mg/kg, between 0.5 mg/kg and 1.5 mg/kg, between 0.5mg/kg and 1 mg/kg, between 1 mg/kg and 1.5 mg/kg, between 1 mg/kg and 2mg/kg, between 1 mg/kg and 2.5 mg/kg, between 1 mg/kg and 3 mg/kg,between 1 mg/kg and 2.5 mg/kg, or between 1 mg/kg and 5 mg/kg.

In an embodiment, the antibody molecule is administered to the subjectat a fixed dose between 10 mg and 1000 mg, e.g., between 10 mg and 500mg, between 10 mg and 250 mg, between 10 mg and 150 mg, between 10 mgand 100 mg, between 10 mg and 50 mg, between 250 mg and 500 mg, between150 mg and 500 mg, between 100 mg and 500 mg, between 50 mg and 500 mg,between 25 mg and 250 mg, between 50 mg and 150 mg, between 50 mg and100 mg, between 100 mg and 150 mg. between 100 mg and 200 mg, or between150 mg and 250 mg.

In an embodiment, the antibody molecule is administered once a week,twice a week, once every two weeks, once every three weeks, once everyfour weeks, once every eight weeks, once a month, once every two months,or once every three months.

In an embodiment, administration of the antibody molecule reduces thelevel of IgA in a peripheral tissue, e.g., in serum, mucosal tissue,bone marrow, or any combination thereof.

In an embodiment, administration of the antibody molecule reduces thelevel of IgA1. In an embodiment, administration of the antibody moleculereduces the level of IgA1 in polymeric form (pIgA1). In an embodiment,administration of the antibody molecule reduces the level of IgA1 withO-linked glycosylation variants (e.g., aberrant or reduced compositionof galactose in CH1 hinge region).

In an embodiment, the method further comprises determining the level ofIgA in a peripheral tissue sample from the subject, e.g., chosen fromserum, mucosal tissue, or bone marrow.

In an embodiment, the method further comprises administering to thesubject a second therapy for IgA nephropathy. In an embodiment, thesecond therapy is chosen from an angiotensin-converting enzyme (ACE)inhibitor, an angiotensin receptor blocker (ARB), omega-3 fatty acids,an immunosuppressant (e.g., a corticosteroid, e.g., prednisone), astatin, mycophenolate mofetil, or any combination thereof.

In an aspect, the disclosure features a method of treating diabeticnephropathy, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating diabetic nephropathy.

In an aspect, the disclosure features a method of treating cancer, themethod comprising administering to a subject in need thereof aneffective amount of an antibody molecule described herein or acomposition described herein, thereby treating cancer.

In an embodiment, the cancer is a hematological cancer. In anembodiment, the hematological cancer is chosen from B-cell non-Hodgkin'slymphoma, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,multiple myeloma, Waldenström macroglobulinemia, or lymphoplasmacyticlymphoma. In an embodiment, the cancer is a multiple myeloma.

In an aspect, the disclosure features a method of treating animmunoproliferative disorder, the method comprising administering to asubject in need thereof an effective amount of an antibody moleculedescribed herein or a composition described herein, thereby treating theimmunoproliferative disorder.

In an embodiment, the immunoproliferative disorder is monoclonal IgAhypergammaglobulinemia.

In an aspect, the disclosure features a method of treating vasculitis,the method comprising administering to a subject in need thereof aneffective amount of an antibody molecule described herein or acomposition described herein, thereby treating vasculitis.

In an embodiment, the vasculitis is kidney vasculitis. In an embodiment,the vasculitis is an IgA associated vasculitis (e.g., Henoch-Schonleinpurpura) or post-streptococcal glomerulonephritis.

In an aspect, the disclosure features a method of treating an autoimmunedisorder, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating the autoimmunedisorder.

In an embodiment, the autoimmune disorder is chosen from rheumatoidarthritis, systemic lupus erythematosus, a linear IgA bullous disease(e.g., linear immunoglobulin A (IgA) dermatosis), or IgA-mediatedepidermolysis bullosa acquisita (EBA).

In an aspect, the disclosure features a method of treating IgApemphigus, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating IgA pemphigus.

In an aspect, the disclosure features a method of treating celiacdisease, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating celiac disease.

In an aspect, the disclosure features a method of treating alcoholiccirrhosis, the method comprising administering to a subject in needthereof an effective amount of an antibody molecule described herein ora composition described herein, thereby treating alcoholic cirrhosis.

In an aspect, the disclosure features a method of reducing the level ofIgA in a cell or subject, the method comprising contacting the cell orsubject, or administering to a subject in need thereof an effectiveamount of, an antibody molecule described herein or a compositiondescribed herein, thereby reducing the level of IgA.

In an embodiment, the antibody molecule is administered to the subjectintravenously.

In an embodiment, the antibody molecule is administered to the subjectat a dose between 0.1 mg/kg and 50 mg/kg, e.g., between 0.2 mg/kg and 25mg/kg, between 0.5 mg/kg and 10 mg/kg, between 0.5 mg/kg and 5 mg/kg,between 0.5 mg/kg and 3 mg/kg, between 0.5 mg/kg and 2.5 mg/kg, between0.5 mg/kg and 2 mg/kg, between 0.5 mg/kg and 1.5 mg/kg, between 0.5mg/kg and 1 mg/kg, between 1 mg/kg and 1.5 mg/kg, between 1 mg/kg and 2mg/kg, between 1 mg/kg and 2.5 mg/kg, between 1 mg/kg and 3 mg/kg,between 1 mg/kg and 2.5 mg/kg, or between 1 mg/kg and 5 mg/kg.

In an embodiment, the antibody molecule is administered to the subjectat a fixed dose between 10 mg and 1000 mg, e.g., between 10 mg and 500mg, between 10 mg and 250 mg, between 10 mg and 150 mg, between 10 mgand 100 mg, between 10 mg and 50 mg, between 250 mg and 500 mg, between150 mg and 500 mg, between 100 mg and 500 mg, between 50 mg and 500 mg,between 25 mg and 250 mg, between 50 mg and 150 mg, between 50 mg and100 mg, between 100 mg and 150 mg. between 100 mg and 200 mg, or between150 mg and 250 mg.

In an embodiment, the antibody molecule is administered once a week,twice a week, once every two weeks, once every three weeks, once everyfour weeks, once every eight weeks, once a month, once every two months,once every three months.

In an embodiment, administration of the antibody molecule reduces thelevel of IgA in a peripheral tissue, e.g., in serum, mucosal tissue,bone marrow, or any combination thereof.

In an embodiment, administration of the antibody molecule reduces thelevel of IgA1. In an embodiment, administration of the antibody moleculereduces the level of IgA1 in polymeric form (pIgA1). In an embodiment,administration of the antibody molecule reduces the level of IgA1 withO-linked glycosylation variants (e.g., aberrant or reduced compositionof galactose in CH1 hinge region).

In an aspect, the disclosure features use of an antibody moleculedescribed herein or a composition described herein in the treatment, orin the manufacture of a medicament for the treatment, of a disorderdescribed herein.

In another aspect, the disclosure features an antibody moleculedescribed herein or a composition described herein for use in thetreatment of a disorder described herein.

In an aspect, the disclosure features a method of detecting an APRILmolecule, the method comprising contacting a cell or a sample from asubject with an antibody molecule described herein, thereby detectingthe APRIL molecule.

In an embodiment, the antibody molecule is coupled with a detectablelabel. In an embodiment, the APRIL molecule is detected in vitro or exvivo. In another embodiment, the APRIL molecule is detected in vivo.

The disclosure contemplates all combinations of any one or more of theforegoing aspects and/or embodiments, as well as combinations with anyone or more of the embodiments set forth in the detailed description andexamples.

Other features, objects, and advantages of the compositions and methodsherein will be apparent from the description and drawings, and from theclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B depict the anti-APRIL antibody profiling from mouse-derivedhybridomas. CD-1 mice were immunized with recombinant multimeric APRIL(human or mouse) as described. The splenocytes from anti-APRILseropositive mice were immortalized through myeloma fusion to generatehybridomas. ELISA-based screening methods were used for evaluatinganti-APRIL antibodies present in conditioned media of immunoglobulinproducing hybridomas. Cell culture supernatants were initially screenedboth for binding to target (APRIL) by indirect ELISA and for functionalactivity with respect to ability to block interaction of APRIL with therecombinant, soluble human TNF receptor TACI-Fc (blocking ELISA).Screening against both human and mouse APRIL was carried out to identifypotentially cross-reactive antibodies. Relative activities are based onsingle point measurements following normalization of immunoglobulinconcentration to 10 μg/mL when possible. APRIL immunogen for final tailvein boost is noted in bold. Hybridoma-derived antibodies lackingblocking activity to either human or mouse APRIL (as initially definedby less than 10% receptor blocking in this first-pass screening assay)are not included in this summary table. Ig isotypes for selecthybridomas are noted.

FIGS. 2A-2B depict the APRIL receptor blocking activity of exemplaryanti-APRIL antibodies. Functional activities of select anti-APRILantibodies purified from mouse-derived hybridoma clones were assessed byELISA using recombinant TACI-Fc as soluble receptor. Assay involves twosteps: 1) preincubation of APRIL with varying concentrations of purifiedmouse antibody; 2) subsequent measurement of APRIL binding toimmobilized TACI-Fc as quantified by ELISA using the appropriatesecondary antibody for detection of epitope tagged APRIL. Interferenceof APRIL-receptor binding was measured as a loss of A450. Hybridomaantibodies are depicted by solid symbols. Control and comparatorantibodies are depicted by open symbols. Apry-1-1 represents amouse-specific blocking antibody used as a control. Human neutralizingantibodies 0201 and 1313 were likewise used as controls and forcomparative purposes to antibodies described in the scientificliterature. Data presented is representative of assay and method forassessing antibody inhibition (receptor blocking). FIG. 2A (humanAPRIL); FIG. 2B (mouse APRIL). IC₅₀ values are reported in FIG. 3.

FIG. 3 depicts the activity profiles of select, purified mouse derivedanti-APRIL antibodies. Binding and blocking activities are extrapolatedfrom data summarized in FIGS. 2A-2B and are based on a non-linearregression of antibody titrations with 3 parameter curve fitting usingGraphpad Prism. Dashes indicate no activity.

FIG. 4 depicts the inhibition of APRIL-mediated TACI signaling in HEK293 cells. Functional inhibition of human APRIL-mediated receptoractivation was assessed using a 293-derived cell line with stablytransfected NF-κB reporter and transiently transfected, human APRILreceptor TACI. HA-tagged GCN4 human APRIL (R&D Systems) was used assource of APRIL. Pre-existing mAb 1313 (human specific, withpre-established blocking activity) was used as a positive control; mousespecific anti-APRIL antibody Apry-1-1 was used as a negative control.Data is illustrative of an orthogonal, biologically relevant assay toassess anti-APRIL activity of mouse derived antibodies.

FIG. 5 depicts the binding of anti-APRIL antibodies to human APRIL.Relative binding of select anti-APRIL antibodies was measured byindirect ELISA. Select antibodies based on prior hybridoma screeningwere recombinantly produced (based on immunoglobin VH and VL genesequencing) as described. HA-tagged GCN4 human APRIL R&D Systems wasused as source of APRIL. Binding data was analyzed by non-linearregression using a three parameter fit. MAbs 1313, 0201, and Aprily-5were included for comparative purposes; Apry-1-1 was used as a negativecontrol. Extrapolated EC₅₀ values are summarized in FIG. 6.

FIG. 6 depicts the relative binding affinities of select anti-APRILantibodies. Data was derived from indirect ELISA (summarized in FIG. 5).Dashes indicate no binding activity.

FIG. 7 depicts the antibody inhibition of APRIL binding to TACI. Assayis based on blocking ELISA using recombinant human APRIL (R&D Systems)and Human TACI-Fc. Inhibition was analyzed by non-linear regressionusing a four parameter fit. MAbs 1313 and 0201 were used as controls andfor comparative purposes. Non-neutralizing anti-APRIL mAb Aprily-5 wasused as a negative control.

FIG. 8 depicts the antibody inhibition of APRIL binding to BCMA. Assayis based on blocking ELISA using recombinant human APRIL and HumanBCMA-Fc. See the description of FIG. 7 for details.

FIG. 9 depicts antibody inhibition of APRIL binding to both humanTACI-Fc and human BCMA-Fc. Relative inhibitory activities aresummarized. Data derived from non-linear regression analyses of antibodyinhibition curves depicted in FIGS. 7-8 using a 4-parameter fit. %inhibition was normalized to the no antibody control (100% inhibition)following subtraction of background (0% inhibition). Dashes representlack of calculated IC₅₀ values due to poor or zero blocking activitymeasured.

FIGS. 10A-10B depict APRIL species cross reactivity of anti-APRILantibodies. Anti-APRIL antibodies with blocking activity (summarized inFIG. 9) were assessed for ability to block both human and mouse APRILbinding to human TACI-Fc and BCMA-Fc. Recombinant mouse and human APRILwith otherwise identical HA-tagged GCN4 N-terminal fusions (R&D Systems)were used as receptor ligands. Select data is included for illustrativepurposes. Antibodies 3530 and 3525 demonstrated any cross-speciesactivity with respect to TACI-Fc receptor blocking (FIG. 10A). Analogouscross-neutralization with respect to APRIL binding to BCMA-Fc was onlypartially achieved (FIG. 10B). Neutralizing Antibody 1313 (humanspecific) and antibody Apry-1-1 (mouse specific) were used as controls.Closed symbols, human APRIL; open symbols, mouse APRIL.

FIGS. 11A-11B depict antibody Inhibition of APRIL-mediated receptorsignaling. Inhibition of APRIL-receptor mediated NF-κB intracellularsignaling was evaluated using the HEK 293 NF-κB reporter cell linefollowing transient transfection of either full-length human TNF familyreceptors TACI or BCMA full-length cDNA expression vectors. Data arenormalized to activity vs. no antibody treatment. Scale of Y axisdisplayed ranges from 0 to 1. Inhibition of APRIL-mediated receptorsignaling was measured at three different antibody concentrations (0.08μg/mL, 0.4 μg/mL, and 10 μg/mL). FIG. 11A shows the inhibition ofTACI-mediated NFB signaling; FIG. 11B shows the inhibition of BCMAmediated NF-κB signaling.

FIGS. 12A-12B depict in vivo potency of an anti-APRIL antibody inreducing serum IgA levels. The suitability of use of anti-APRIL antibodyfor modulating IgA production in vivo was evaluated based directly on areduction of serum IgA levels following the administration of aneutralizing anti-APRIL antibody in a laboratory rodent model. For thispurpose mouse-APRIL specific, blocking antibody Apry-1-1 (Adipogen)hitherto used as a control for assessing anti-APRIL antibody activity invitro was also used as a test antibody to demonstrate proof-of-concept.Age-matched male B6C3F1 mice (6-10 weeks old) were dosed with 20 mg/kgantibody two times a week via i.p. injection for a total of 8 weeks.Saline for injection was used as the negative (vehicle) control (VC).Serum isotype specific immunoglobulin levels (IgG, IgM, and IgA) weremonitored individually by ELISA approximately every 12 days. FIG. 12Ashows the effect of treatment on total serum IgA levels; FIG. 12B showsthe effect of treatment vs. control on total immunoglobulin levels insera. Data represent summation of IgG+IgA+IgM levels measuredseparately.

FIG. 13 depicts sequence alignment of human and mouse APRIL (SEQ ID NOS:85 and 91, respectively). Sequence alignments of soluble APRIL weredetermined using CLUSTALW Amino acid sequences correspond to SwissProtaccession numbers 075888 (human) and Q9D777 (mouse).

FIG. 14 depicts the structural definition of exemplary APRIL epitope forantibody targeting. A space filling model of trimeric APRIL is depicted.Exemplary (spatially defined) region to be targeted by an antibodymolecule is depicted in darker gray and indicated by arrow. This epitopeincludes positions in APRIL that bridge monomers. Differences betweenmouse and human APRIL sequences are highlighted with corresponding aminoacid differences at these positions noted. The putative N-glycosylationsite (N124) is noted in black and indicated by arrow.

FIG. 15 depicts the structural definition of exemplary APRIL epitope forantibody targeting. Ribbon model of trimeric APRIL is depicted and coreepitope for anti-APRIL targeting is highlighted in dark gray.

FIG. 16 depicts the binding of exemplary anti-APRIL antibodies to humanAPRIL. Relative binding of exemplary anti-APRIL antibodies was measuredby indirect ELISA. Extrapolated EC₅₀ values are summarized in FIG. 17.

FIG. 17 depicts the relative binding affinities of exemplary anti-APRILantibodies. Data was derived from indirect ELISA (summarized in FIG.16).

FIGS. 18A-18B depict the antibody inhibition of APRIL-mediated receptorsignaling. Inhibition of APRIL-receptor mediated NFκB intracellularsignaling was evaluated using the HEK 293 NFκB reporter cell linefollowing transient transfection of either full-length human TNF familyreceptors TACI (FIG. 18A) or BCMA (FIG. 18B) full-length cDNA expressionvectors. Exemplary antibodies were shown for illustrative purposes.

FIGS. 19A-19B depict the antibody inhibition of APRIL binding to TNFSFreceptors TACI (FIG. 19A) and BCMA (FIG. 19B). Assay is based onblocking ELISA using recombinant human APRIL (R&D Systems) and HumanTACI-Fc. Inhibition was analyzed by non-linear regression using a fourparameter fit. IC₅₀ values are summarized in FIG. 20.

FIG. 20 depicts the antibody inhibition of APRIL binding to both humanTACI-Fc and human BCMA-Fc (summary of relative inhibitory activities).Data derived from non-linear regression analyses of antibody inhibitioncurves depicted in FIG. 19 using a 4-parameter fit. % inhibition wasnormalized to the no antibody control (100% inhibition) followingsubtraction of background (0% inhibition). Dashes represent lack ofcalculated IC₅₀ values due to poor or partial blocking activitymeasured.

FIGS. 21A-21B depict APRIL species cross blocking activities ofanti-APRIL antibodies. Ability of anti-APRIL antibodies to block bindingof both human (FIG. 21A) and mouse (FIG. 21B) APRIL to BCMA wasevaluated by ELISA. Respective blocking activities of exemplaryantibodies (3833, 4540, 3530, 3631, and 3732) with previously determinedcross-species (mouse and human) APRIL binding are shown.

FIG. 22 depicts human APRIL site-directed variants used for epitopemapping. APRIL is depicted as a trimer. Typical epitope containing CRD2high affinity receptor binding site is depicted in dark gray. Positionsof amino acid changes are noted with wildtype amino acid precedingnumber and mutation following (e.g., R233G represents mutation ofarginine at position 233 to glycine).

FIGS. 23A-23B depict epitope mapping of antibody 4035 (FIG. 23A)(comparison is made to reference antibody 1313; see FIG. 23B). Antibodybinding to human and mouse variants was assessed by ELISA. FLAG-taggedAPRIL was captured from cell culture media using anti-FLAG antibody.Human APRIL variants are depicted as open bars; mouse APRIL variants aredepicted as solid bars.

FIGS. 24A-24B depict epitope mapping of antibody 2419 (FIG. 24A)(comparison is made to reference antibody 1313; see FIG. 24B). Antibodybinding to human and mouse variants was assessed by ELISA. Human APRILvariants are depicted as open bars; mouse APRIL variants are depicted assolid bars.

FIGS. 25A-25B depict epitope mapping of antibody 3833 (FIG. 25A)(comparison is made to reference antibody 1313; see FIG. 25B). Antibodybinding to human and mouse variants was assessed by ELISA. FLAG-taggedAPRIL was captured from cell culture media using anti-FLAG antibody.Human APRIL variants are depicted as open bars; mouse APRIL variants aredepicted as solid bars.

FIG. 26 depicts differentiated epitope mapping of anti-APRIL antibodiesby site directed mutagenesis. Primary characterization of human APRILbinding site was carried out by site-directed mutagenesis of selectamino acid positions within APRIL followed by evaluation of antibodybinding to these variants by ELISA. Exemplary data for three anti-APRILantibodies 4035 (solid circles), 2419 (solid squares), and 1313 (opentriangles) are shown for illustrative purposes.

FIGS. 27A-27B depict the binding of exemplary anti-APRIL antibodies tohuman APRIL. Antibodies include humanized variants of mouse antibodies4035 (FIG. 27A) and 2419 (FIG. 27B). Relative binding of exemplaryanti-APRIL antibodies was measured by indirect ELISA. Comparison ofhumanized anti-APRIL antibodies to parental (non-humanized) mouseantibodies is made for comparative purposes. Extrapolated EC₅₀ valuesare summarized in FIG. 29A.

FIGS. 28A-28B depict the binding of humanized variant of human-mousecross reactive antibody 4540-063 to both human APRIL (FIG. 28A) andmouse APRIL (FIG. 28B). Relative binding of exemplary anti-APRILantibody was measured by indirect ELISA. Comparison of parental(non-humanized) antibody is made for comparative purposes. ExtrapolatedEC₅₀ values are summarized in FIG. 29B.

FIGS. 29A-29B depict the relative binding affinities of exemplaryanti-APRIL antibodies. Data (EC₅₀ values) were derived from indirectELISA (summarized in FIGS. 27A-27B and FIGS. 28A-28B). FIG. 29A showsrelative binding affinities of exemplary, humanized anti-APRILantibodies based on 2419 and 4035. FIG. 29B shows relative bindingaffinities of cross-reactive antibody 4540 and its humanized variant4540-063. Binding data for both human and mouse APRIL are included.

FIGS. 29C-29D depict the binding affinity of antibody 2419-1406 and4035-062 to trimeric human APRIL measured by ELISA. Trimer wasstabilized by N-terminal fusion of APRIL with isoleucine zipper (GCN4)domain Binding of APRIL to human TACI-Fc is shown for comparativepurposes. The EC₅₀ values derived from the binding curves depicted inFIG. 29C are summarized in FIG. 29D.

FIGS. 30A-30B depict antibody inhibition of APRIL binding to TNFSFreceptors TACI and BCMA by humanized IgG2K variants of parental, murinederived antibody 2419. Assay is based on receptor blocking ELISA usingrecombinant human APRIL (R&D Systems) and either human TACI-Fc (FIG.30A) or BCMA-Fc (FIG. 30B). Parental, chimeric 2419 (mouse VH-VL graftedon to human IgG1κ constant regions) was included for comparativepurposes as was chimeric anti-human APRIL antibody 4035. Inhibition wasanalyzed by non-linear regression using a four parameter curve fitfollowing normalization to 100% activity (no antibody control). IC₅₀values are summarized in FIG. 33.

FIGS. 31A-31B depict the inhibition of APRIL binding to TNFSF receptorsTACI (FIG. 31A) and BCMA (FIG. 31B) by additional humanized variants of2419 (IgG2K) 2419-0205 and 2419-1406 and humanized variant (4035-062) ofparental antibody 4035. Humanized 4035-062 is of the IgG1κ subtype.Chimeric, non-humanized versions of mouse derived antibodies 4035 and2419, and 1313 are included for comparative purposes. mAb1313 is acontrol anti-APRIL antibody. TACI-Fc and BCMA-Fc were used. IC₅₀ valuesare summarized in FIG. 33.

FIGS. 32A-32B depict the antibody inhibition of APRIL binding to TNFSFreceptors TACI (FIG. 32A) and BCMA (FIG. 32B) by humanized variants ofmouse/human APRIL cross neutralizing antibody 4540. Humanized antibody4540 is of the IgG1κ subtype. Parental 4540 (non-humanized chimera) andhumanized 4035-062 (FIGS. 30A-30B) are included for comparativepurposes. Inhibition was analyzed by non-linear regression using a fourparameter curve fit as described for FIGS. 29A-29B and FIGS. 30A-30B.IC₅₀ values are also summarized in FIG. 33.

FIG. 33 depicts IC₅₀ values of antibody inhibition of APRIL-receptorbinding. IC₅₀ values are based on a non-linear regression analysis ofdata from FIGS. 30A-32B. Data are also normalized (relative activity) toparental, mouse derived antibody 2419.

FIGS. 34A-34B depict the antibody inhibition of APRIL-mediated receptorsignaling. Inhibition of APRIL-receptor mediated NFκB intracellularsignaling was evaluated using the HEK 293 NFκB reporter cell linefollowing transient transfection of either full-length human TNF familyreceptors TACI or BCMA cDNA expression vectors. Data are normalized tono antibody control (100%). FIG. 34A shows inhibition of TACI-mediatedNFκB signaling. FIG. 34B shows inhibition of BCMA-mediated-NFκBsignaling.

FIG. 35 depicts the approximate IC₅₀ values of antibody inhibition ofAPRIL-mediated receptor signaling. Data are extrapolated from FIGS.34A-34B based on a non-linear regression analysis using a variableslope, three parameter fit of antibody concentration vs. response.Negative antibody control (no APRIL binding) demonstrated no activity inthis assay (data not shown).

FIG. 36 depicts analysis of APRIL antibody binding reactivity to othermembers of the TNFSF13 family of cytokines. A select panel ofrecombinant TNFSF-related cytokines (Adipogen) was used to test forantibody cross-reactivity as measured by ELISA. Panel included humanAPRIL (specific target) and structurally related BAFF. Exemplaryantibodies are included for illustrative purposes. As predicted, strongbinding of anti-APRIL antibodies to human APRIL was detected.Cross-reactivity to BAFF and other members other than the target (humanAPRIL), however, was generally not substantially detected above assaybackground (measured here using BSA only and assay diluent, 1×PBScontrols). Antibody 4338, a previously identified BAFF cross-reactiveantibody, was used as a positive (BAFF-reactive) control. A controlantibody, mAb1313, was also included.

FIGS. 37A-37C depict the minimal protein cross-reactivity of mAb2419-1406 and mAb 4035-062 in an extensive array of over 4500heterologously expressed human membrane proteins in an HEK293-basedassay and the confirmatory/secondary screen. An example of proteinexpression array design is shown in FIG. 37A. FIGS. 37B-37C depict theconfirmatory/secondary screen of 12 proteins. Expression levels ofsecondary screening array of 12 human membrane proteins in 293 cellsbased on GFP are shown in left panels of FIGS. 37B-37C. Antibody bindingto this same array is shown in right panels of FIGS. 37B-37C.

FIG. 38A depicts the molecular engagement of the anti-APRIL mAb 2419binding to APRIL based on low resolution X-ray co-crystallographic dataof human APRIL (amino acids 115-250) and Fab region of mouse 2419.Structure was solved by molecular replacement using mouse APRILdescribed in the protein structure database. 2419 epitope within APRILis indicated by arrow. Variable heavy and light chains of mAb 2419 arealso indicated. Structure of APRIL is depicted as a trimer.

FIG. 38B depicts residues within APRIL that comprise a subset of the2419 epitope. This structural depiction of the 2419 epitope alsohighlights the fact that 2419 binds to a non-linear, quaternary epitopespanning two different monomers of APRIL within a larger trimericcomplex depicted here as monomer A and monomer B. Epitope on monomer Aand epitope on monomer B are indicated. 2419 epitope substantiallyoverlaps with the high affinity receptor binding site (CRD2) and loweraffinity receptor binding site (CRD1) critical for APRIL-mediatedreceptor signaling. CRD2 receptor binding site and CRD1 receptor bindingsite are outlined and indicated.

FIGS. 39A-39B depict the thermal stability of antibodies mAb 2419-1406and 4035-062 as measured using Sypro-Orange® fluorescence scanningassay. The thermal melting temperatures (Tm values) for both 2419-1406and 4035-062 are listed in FIG. 39B.

FIGS. 40A-40B depict the PK profiles of mAb 2419-1406 and 4035-062 inhumanized FcRn transgenic mouse strain tg32. Tg32 mice were administereda single 5 mg/kg dose of mAb 2419-1406 or mAb 4035-062 by intravenousinjection. Antibody levels in sera were determined by ELISA followingtimepoints taken out to 20 days. PK values are listed in FIG. 40B.

FIG. 41 depicts the reduction of basal serum IgA levels in mice treatedwith mAb 4540 and mAb 3833. 11 week old C57/BL6 mice weresub-chronically dosed (1× weekly by i.p injection) with 20 mg/kg of mAb4540 or isotype control antibody for seven weeks. Basal serum levels oftotal IgA were quantified by ELISA. Median IgA levels graphed; N=5 miceper group.

DETAILED DESCRIPTION

Disclosed herein are antibody molecules that bind to APRIL, e.g., humanAPRIL, mouse APRIL, or both, with high affinity and specificity.Advantageously, several of the antibody molecules describe herein haveimproved ability to reduce (e.g., inhibit, block, or neutralize) one ormore biological activities of APRIL. Nucleic acid molecules encoding theantibody molecules, expression vectors, host cells, compositions (e.g.,pharmaceutical compositions), kits, and methods for making the antibodymolecules, are also provided. The antibody molecules and pharmaceuticalcompositions disclosed herein can be used (alone or in combination withother agents or therapeutic modalities) to treat, prevent and/ordiagnose disorders and conditions, e.g., disorders and conditionsassociated with APRIL, e.g., IgA nephropathy.

Definitions

As used herein, the articles “a” and “an” refer to one or to more thanone (e.g., to at least one) of the grammatical object of the article.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or”, unless context clearly indicates otherwise.

“About” and “approximately” shall generally mean an acceptable degree oferror for the quantity measured given the nature or precision of themeasurements. Exemplary degrees of error are within 20 percent (%),typically, within 10%, and more typically, within 5% of a given value orrange of values.

The compositions and methods disclosed herein encompass polypeptides andnucleic acids having the sequences specified, or sequences substantiallyidentical or similar thereto, e.g., sequences at least 85%, 90%, 95%identical or higher to the sequence specified.

In the context of an amino acid sequence, the term “substantiallyidentical” is used herein to refer to a first amino acid that contains asufficient or minimum number of amino acid residues that are i)identical to, or ii) conservative substitutions of aligned amino acidresidues in a second amino acid sequence such that the first and secondamino acid sequences can have a common structural domain and/or commonfunctional activity. For example, amino acid sequences that contain acommon structural domain having at least about 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., asequence provided herein.

In the context of nucleotide sequence, the term “substantiallyidentical” is used herein to refer to a first nucleic acid sequence thatcontains a sufficient or minimum number of nucleotides that areidentical to aligned nucleotides in a second nucleic acid sequence suchthat the first and second nucleotide sequences encode a polypeptidehaving common functional activity, or encode a common structuralpolypeptide domain or a common functional polypeptide activity. Forexample, nucleotide sequences having at least about 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence,e.g., a sequence provided herein.

The term “functional variant” refers polypeptides that have asubstantially identical amino acid sequence to the naturally-occurringsequence, or are encoded by a substantially identical nucleotidesequence, and are capable of having one or more activities of thenaturally-occurring sequence.

Calculations of homology or sequence identity between sequences (theterms are used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences, or of twonucleic acid sequences, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in one or both of a first and asecond amino acid or nucleic acid sequence for optimal alignment andnon-homologous sequences can be disregarded for comparison purposes). Ina typical embodiment, the length of a reference sequence aligned forcomparison purposes is at least 30%, e.g., at least 40%, 50%, 60%, e.g.,at least 70%, 80%, 90%, 100% of the length of the reference sequence.The amino acid residues or nucleotides at corresponding amino acidpositions or nucleotide positions are then compared. When a position inthe first sequence is occupied by the same amino acid residue ornucleotide as the corresponding position in the second sequence, thenthe molecules are identical at that position.

The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In some embodiments, the percent identity between two aminoacid sequences is determined using the Needleman and Wunsch ((1970) J.Mol. Biol. 48:444-453) algorithm which has been incorporated into theGAP program in the GCG software package (available at gcg.com), usingeither a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16,14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Incertain embodiments, the percent identity between two nucleotidesequences is determined using the GAP program in the GCG softwarepackage (available at gcg.com), using a NWSgapdna.CMP matrix and a gapweight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or6. One suitable set of parameters (and the one that should be usedunless otherwise specified) are a Blossum 62 scoring matrix with a gappenalty of 12, a gap extend penalty of 4, and a frameshift gap penaltyof 5.

The percent identity between two amino acid or nucleotide sequences canbe determined using the algorithm of E. Meyers and W. Miller ((1989)CABIOS, 4:11-17) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a“query sequence” to perform a search against public databases to, forexample, identify other family members or related sequences. Suchsearches can be performed using the NBLAST and XBLAST programs (version2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLASTnucleotide searches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to a nucleicacid as described herein. BLAST protein searches can be performed withthe XBLAST program, score=50, wordlength=3 to obtain amino acidsequences homologous to protein molecules described herein. To obtaingapped alignments for comparison purposes, Gapped BLAST can be utilizedas described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402.When utilizing BLAST and gapped BLAST programs, the default parametersof the respective programs (e.g., XBLAST and NBLAST) can be used. Seewww.ncbi.nlm.nih.gov.

As used herein, the term “hybridizes under low stringency, mediumstringency, high stringency, or very high stringency conditions”describes conditions for hybridization and washing. Guidance forperforming hybridization reactions can be found in Current Protocols inMolecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which isincorporated by reference. Aqueous and nonaqueous methods are describedin that reference and either can be used. Specific hybridizationconditions referred to herein are as follows: 1) low stringencyhybridization conditions in 6× sodium chloride/sodium citrate (SSC) atabout 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at50° C. (the temperature of the washes can be increased to 55° C. for lowstringency conditions); 2) medium stringency hybridization conditions in6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1%SDS at 60° C.; 3) high stringency hybridization conditions in 6×SSC atabout 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65°C.; and preferably 4) very high stringency hybridization conditions are0.5M sodium phosphate, 7% SDS at 65° C., followed by one or more washesat 0.2×SSC, 1% SDS at 65° C. Very high stringency conditions 4) aresuitable conditions and the ones that should be used unless otherwisespecified.

It is understood that the molecules described herein may have additionalconservative or non-essential amino acid substitutions, which do nothave a substantial effect on their functions.

The term “amino acid” is intended to embrace all molecules, whethernatural or synthetic, which include both an amino functionality and anacid functionality and capable of being included in a polymer ofnaturally-occurring amino acids. Exemplary amino acids includenaturally-occurring amino acids; analogs, derivatives and congenersthereof; amino acid analogs having variant side chains; and allstereoisomers of any of any of the foregoing. As used herein the term“amino acid” includes both the D- or L-optical isomers andpeptidomimetics.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a similar sidechain. Families of amino acid residues having similar side chains havebeen defined in the art. These families include amino acids with basicside chains (e.g., lysine, arginine, histidine), acidic side chains(e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine),nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,proline, phenylalanine, methionine, tryptophan), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine).

The terms “polypeptide,” “peptide” and “protein” (if single chain) areused interchangeably herein to refer to polymers of amino acids of anylength. The polymer may be linear or branched, it may comprise modifiedamino acids, and it may be interrupted by non-amino acids. The termsalso encompass an amino acid polymer that has been modified; forexample, disulfide bond formation, glycosylation, lipidation,acetylation, phosphorylation, or any other manipulation, such asconjugation with a labeling component. The polypeptide can be isolatedfrom natural sources, can be a produced by recombinant techniques from aeukaryotic or prokaryotic host, or can be a product of syntheticprocedures.

The terms “nucleic acid,” “nucleic acid sequence,” “nucleotidesequence,” or “polynucleotide sequence,” and “polynucleotide” are usedinterchangeably. They refer to a polymeric form of nucleotides of anylength, either deoxyribonucleotides or ribonucleotides, or analogsthereof. The polynucleotide may be either single-stranded ordouble-stranded, and if single-stranded may be the coding strand ornon-coding (antisense) strand. A polynucleotide may comprise modifiednucleotides, such as methylated nucleotides and nucleotide analogs. Thesequence of nucleotides may be interrupted by non-nucleotide components.A polynucleotide may be further modified after polymerization, such asby conjugation with a labeling component. The nucleic acid may be arecombinant polynucleotide, or a polynucleotide of genomic, cDNA,semisynthetic, or synthetic origin which either does not occur in natureor is linked to another polynucleotide in a non-natural arrangement.

The term “isolated,” as used herein, refers to material that is removedfrom its original or native environment (e.g., the natural environmentif it is naturally occurring). For example, a naturally-occurringpolynucleotide or polypeptide present in a living animal is notisolated, but the same polynucleotide or polypeptide, separated by humanintervention from some or all of the co-existing materials in thenatural system, is isolated. Such polynucleotides could be part of avector and/or such polynucleotides or polypeptides could be part of acomposition, and still be isolated in that such vector or composition isnot part of the environment in which it is found in nature.

As used herein, the term “treat,” e.g., IgA nephropathy, means that asubject (e.g., a human) who has a disorder, e.g., IgA nephropathy,and/or experiences a symptom of a disorder, e.g., IgA nephropathy, will,in an embodiment, suffer less a severe symptom and/or recover fasterwhen an antibody molecule is administered than if the antibody moleculewere never administered. In an embodiment, when IgA nephropathy istreated, a kidney biopsy will show less or no IgA deposits, e.g., in theform of immune complexes in the mesangium of the kidney, after effectivetreatment for IgA nephropathy. For example, a diagnostic assay usingimmunofluorescence or electron microscopy will detect less no IgAdeposits in a biological sample of a subject after administration of anantibody molecule described herein for the effective treatment of IgAnephropathy. Other assays, urine tests, blood tests, iothalamateclearance tests, or kidney imaging (e.g., ultrasound, X-rays, orcystoscopy), can also be used to monitor treatment in a patient, or todetect the presence, e.g., decreased presence (or absence), of a symptomof IgA nephropathy, after treatment of IgA nephropathy in the subject.Treatment can, e.g., partially or completely, alleviate, ameliorate,relieve, inhibit, or reduce the severity of, and/or reduce incidence,and optionally, delay onset of, one or more manifestations of theeffects or symptoms, features, and/or causes of a disorder, e.g., IgAnephropathy. In an embodiment, treatment is of a subject who does notexhibit certain signs of a disorder, e.g., IgA nephropathy, and/or of asubject who exhibits only early signs of a disorder, e.g., nephropathy.In an embodiment, treatment is of a subject who exhibits one or moreestablished signs of a disorder, e.g., IgA nephropathy. In anembodiment, treatment is of a subject diagnosed as suffering from adisorder, e.g., IgA nephropathy.

As used herein, the term “prevent,” a disorder, e.g., IgA nephropathy,means that a subject (e.g., a human) is less likely to have thedisorder, e.g., IgA nephropathy, if the subject receives the antibodymolecule.

Various aspects of the compositions and methods herein are described infurther detail below. Additional definitions are set out throughout thespecification.

APRIL

APRIL (A PRoliferation Inducing Ligand), also known as CD256, TNF- andAPOL-related Leukocyte Expressed Ligand 2 (TALL-2), or TNF-related DeathLigand 1 (TRDL-1), is a TNF family cytokine encoded by the TumorNecrosis Factor Ligand Superfamily Member 13 (TNFSF13) gene (also knownas APRIL, TALL2, or ZTNF2). APRIL plays a role in a number of biologicalprocesses such as signal transduction, regulation of cell proliferation,and IgA class switching (Hahne et al. (1998) J. Exp. Med. 188:1185-1190(1998); Castigli et al. Proc. Natl. Acad. Sci. U.S.A. 101:3903-3908(2004)).

APRIL is both functionally and structurally related to BAFF (B CellActivating Factor F13B) also known as BLyS (B lymphocyte stimulator).Both cytokines are involved in regulating keys aspects of innate andadaptive immune functions. Both APRIL and BAFF bind the lymphocytereceptors TACI (transmembrane activator and CAML interactor) and BCMA (Bcell maturation antigen). APRIL and BAFF appear to heterologouslyinteract with each other through protein-protein interactions. Whileboth APRIL and BAFF share biochemical (receptor binding), immunologicaland even some structural overlap (e.g., as it relates to thethree-dimensional topology of their respective receptor bindingdomains), the two cytokines, nevertheless, are both structurally andfunctionally distinct. APRIL binds to biologically relevant heparansulfate (present in the extracellular matrices of cells as heparansulfate proteoglycans); BAFF does not. This interaction plays a criticalbiological function with respect to promoting the oligomerization stateof APRIL in concert with its localized interaction with TACI, whichlikewise requires HSPGS for full activity. Unlike BAFF which acts as apotent activator of B cells inclusive of both proliferation anddifferentiation, APRIL would appear to function more particularly withrespect to the modulation of B cell phenotype, e.g., as it relates toIgA production and the differentiation/survival of IgA positive plasmacells. As such, a targeted disruption in APRIL-receptor signaling isexpected to have less perturbative effects on B cell homeostasis andoverall immune function in comparison to other immune relatedtherapeutics that target BAFF (e.g., belimumab) or anti CD20 therapies(e.g., rituximab) that largely target pre and early B cells. APRIL hasalso been shown to be expressed at high levels on other myeloid relatedcells and lymphoid tissues, as well as hematological cancers (e.g.,myeloma, chronic lymphocytic leukemia (CLL)) and solid tumors (e.g.,colon, thyroid, and breast).

Exemplary amino acid and nucleotide sequences of human APRIL aredescribed, e.g., in Hahne et al. J. Exp. Med. 188:1185-1190 (1998); Shuet al. J. Leukoc. Biol. 65:680-683 (1999); Kelly et al. Cancer Res.60:1021-1027(2000); and Pradet-Balade et al. EMBO J. 21:5711-5720(2002).

The amino acid sequence of human APRIL (isoform alpha, also referred toas the “canonical” sequence (SEQ ID NO: 85)) is provided as follows.

>huAPRIL MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSP HGTFLGFVKL

There are several isoforms of human APRIL produced by alternativesplicing.

Isoform beta has the following amino acid sequence (SEQ ID NO: 86):

>sp|O75888-2|TNF13_HUMAN Isoform Beta of Tumornecrosis factor ligand superfamily member 13OS = Homo sapiens GN = TNFSF13MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKNDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPH GTFLGFVKL

The sequence of isoform beta differs from the canonical sequence asfollows: amino acids 113-129 of SEQ ID NO: 85: KQHSVLHLVPINATSKD→N

Isoform gamma has the following amino acid sequence (SEQ ID NO: 87):

>sp|O75888-3|TNF13_HUMAN Isoform Gamma of Tumornecrosis factor ligand superfamily member 13OS = Homo sapiens GN = TNFSF13MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAK LNLSPHGTFLGL

The sequence of isoform gamma differs from the canonical sequence asfollows: amino acids 247-249: Missing.

Isoform 4 has the following amino acid sequence (SEQ ID NO: 88):

>sp|O75888-4|TNF13_HUMAN Isoform 4 of Tumornecrosis factor ligand super family member 13OS = Homo sapiens GN = TNFSF13MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFV KL

The sequence of isoform 4 differs from the canonical sequence asfollows: amino acids 86-113: Missing.

Isoform TWE-PRIL has the following amino acid sequence (SEQ ID NO: 89):

>sp|O43508-2|TNF12_HUMAN Isoform TWE-PRIL ofTumor necrosis factor ligand superfamily member12 OS = Homo sapiens GN = TNFSF12MAARRSQRRRGRRGEPGTALLVPLALGLGLALACLGLLLAVVSLGSRASLSAQEPAQEELVAEEDQDPSELNPQTEESQDPAPFLNRLVRPRRSAPKGRKTRARRAIAAHYEVHPRPGQDGAQAGVDGTVSGWEEARINSSSPLRYNRQIGEFIVTRAGLYYLYCQSSDALEAWENGERSRKRRAVLTQKQKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVK L

Isoform 5 has the following amino acid sequence (SEQ ID NO: 90):

>sp|O75888-5|TNF13_HUMAN Isoform 5 of Tumornecrosis factor ligand superfamily member 13OS = Homo sapiens GN = TNFSF13MGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQSLRREVSRLQGTGGPSQNGEGYPWQSLPEQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPRARAKLNLSPHGTFLGFVKL

The sequence of isoform 5 differs from the canonical sequence asfollows: amino acids 1-17: Missing; amino acids 87-114: Missing.

Other variant and alternative sequences of human APRIL are described,e.g., in The MGC Project Team, Genome Res. 14:2121-2127 (2004); Ota etal. Nat. Genet. 36:40-45 (2004); and Kelly et al. Cancer Res.60:1021-1027 (2000).

As used herein, when an anti-APRIL antibody molecule binds, orsubstantially binds, to human APRIL, it binds, or substantially binds,to one or more isoforms of human APRIL, e.g., one or more isoforms ofhuman APRIL described herein. In an embodiment, the antibody moleculebinds or substantially binds to human APRIL having the amino acidsequence of SEQ ID NO: 85.

Exemplary amino acid and nucleotide sequences of mouse APRIL aredescribed, e.g., in Yu et al. Nat. Immunol. 1:252-256 (2000); Carninciet al. Science 309:1559-1563 (2005); The MGC Project Team, Genome Res.14:2121-2127 (2004); and Bossen et al. J. Biol Chem. 281: 13964-13971(2006).

The amino acid sequence of mouse APRIL isoform 1 (SEQ ID NO: 91) isprovided as follows.

>muAPRIL MPASSPGHMGGSVREPALSVALWLSWGAVLGAVTCAVALLIQQTELQSLRREVSRLQRSGGPSQKQGERPWQSLWEQSPDVLEAWKDGAKSRRRRAVLTQKHKKKHSVLHLVPVNITSKADSDVTEVMWQPVLRRGRGLEAQGDIVRVWDTGIYLLYSQVLFHDVTFTMGQVVSREGQGRRETLFRCIRSMPSDPDRAYNSCYSAGVFHLHQGDIITVKIPRANAKLSLSPHGTF LGFVKL

The amino acid sequence of mouse APRIL isoform 2 (SEQ ID NO: 92) isprovided as follows.

MPASSPGHMGGSVREPALSVALWLSWGAVLGAVTCAVALLIQQTELQSLRREVSRLQRSGGPSQKQGERPWQSLWEQSPDVLEAWKDGAKSRRRRAVLTQKHKKKHSVLHLVPVNITSKDSDVTEVMWQPVLRRGRGLEAQGDIVRVWDTGIYLLYSQVLFHDVTFTMGQVVSREGQGRRETLFRCIRSMPSDPDRAYNSCYSAGVFHLHQGDIITVKIPRANAKLSLSPHGTFL GFVKL

As used herein, when an anti-APRIL antibody molecule binds, orsubstantially binds, to mouse APRIL, it binds, or substantially binds,to one or more isoforms of mouse APRIL, e.g., one or more isoforms ofmouse APRIL described herein. In an embodiment, the antibody moleculebinds or substantially binds to mouse APRIL having the amino acidsequence of SEQ ID NO: 91, SEQ ID NO: 92, or both.

As used herein, when an anti-APRIL antibody molecule does not bind, ordoes not substantially bind, to mouse APRIL, it does not bind, or doesnot substantially bind, to one or more isoforms of mouse APRIL, e.g.,one or more isoforms of mouse APRIL described herein. In an embodiment,the antibody molecule does not bind, or does not substantially bind, tomouse APRIL having the amino acid sequence of SEQ ID NO: 91 or 92. In atypical embodiment, the antibody molecule does not bind, or does notsubstantially bind, to mouse APRIL having the amino acid sequence of SEQID NO: 91 and mouse APRIL having the amino acid sequence of SEQ ID NO:92.

Sequence alignment of exemplary human and mouse APRIL proteins (SEQ IDNOS: 85 and 91, respectively) is shown in FIG. 13.

Epitope

The antibody molecule described herein can bind to an epitope on APRIL(e.g., human APRIL, mouse APRIL, or both). For example, an epitope boundby an antibody molecule described herein can include one or more epitopecontact points described herein.

In an embodiment, the antibody molecule contacts (e.g., binds, orsubstantially binds, to) one or more residues, or one or more regions,as described in any of Tables 3-4 or 6-8, or any of FIGS. 14, 22,23A-23B, 24A-24B, 25A-25B, or 38A-38B.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all) ofthe amino acid residues shown in Table 3. In an embodiment, the antibodymolecule contacts (e.g., binds or substantially binds to) all of theamino acid residues shown in Table 3. For example, the antibodymolecules described herein can contact the amino acid residues shown inTable 3 in a manner that includes binding across two APRIL monomers(e.g., as depicted positionally in Table 3 as A vs. B). While notwishing to be bound by theory, it is believed that in an embodiment, atleast some of the amino acid residues shown in Table 3 contribute tohigh affinity interactions between APRIL and the CDR2 domain of TACI. Inan embodiment, contacting one or more of the amino acid residues inTable 3 with an antibody molecule described herein inhibits, orsubstantially inhibits, binding of APRIL to TACI.

Exemplary human APRIL amino acid residues that can bind to theanti-APRIL antibody molecules described herein are shown in Table 3. Astructural representation of this epitope (e.g., defined both spatiallyand conformationally) is depicted in FIG. 14.

TABLE 3 Exemplary Human APRIL Amino Acid Residues that Bind toAnti-APRIL Antibodies (amino acid numbering based on SEQ ID NO: 85)Monomer Amino Acid Position Amino Acid A 130 Asp A 131 Ser A 132 Asp A174 Val A 175 Thr A 176 Phe A 177 Thr A 178 Met A 179 Gly A 180 Gln A181 Val A 192 Thr A 195 Arg A 196 Cys A 197 Ile A 200 Met A 201 Pro A202 Ser A 208 Tyr A 230 Pro A 231 Arg A 232 Ala A 241 His B 170 Leu B205 Asp B 206 Arg

In another embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,or all) of the amino acid residues shown in Table 4. In anotherembodiment, the antibody molecule contacts (e.g., binds or substantiallybinds to) all of the amino acid residues shown in Table 4. In anembodiment, the antibody molecule binds, or substantially binds to, theC-D loop (e.g., the loop connecting β-sheets C and D), the G-H loop(e.g., the loop connecting β-sheets G and H), or both, on APRIL.

A structural (spatial) representation of this epitope (sometimesreferred herein as “core region”) is depicted in FIG. 15. As shown inFIG. 15, each APRIL protein molecule contains two packed antiparalleleight-stranded β-sheets (A to G), one inner and one outer, in a (3 jellyroll topology. These B sheets are connected by loops that also define(based on secondary structure definitions) a desired epitope. While notwishing to be bound by theory, it is believed that as thesepositions/structures define a subset of key interactions with APRIL andthe CRD2 domain of TACI, optimal inhibition of APRIL binding to TACI bysuch an antibody would be achieved.

TABLE 4 Exemplary Human APRIL Amino Acid Residues that Bind toAnti-APRIL Antibodies (amino acid numbering based on SEQ ID NO: 85)Amino Acid Position Amino Acid 174 Val 175 Thr 176 Phe 177 Thr 178 Met179 Gly 180 Gln 181 Val 230 Pro 231 Arg 232 Ala

In another embodiment, the antibody molecule does not bind to one, two,or all of Asp129, Arg233, or HIS203, on human APRIL (e.g., SEQ ID NO:85). For example, one or more mutations at these positions, e.g.,Asp129Ala, Arg233Asn, His203Asp, or any combination thereof, would notreduce, or substantially reduce, the binding affinity of the antibodymolecule to human APRIL, or the inhibitory effect of the antibodymolecule on a human APRIL activity (e.g., neutralization of APRILbinding to TACI).

In yet another embodiment, the antibody molecule binds, or substantiallybinds, to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues ofhuman APRIL (e.g., SEQ ID NO: 85) from positions 105-114 and/or one ormore (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of mouse APRIL(e.g., SEQ ID NO: 91) from positions 96-105.

In another embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, or all) of the amino acid residues shown inTable 7. In another embodiment, the antibody molecule contacts (e.g.,binds or substantially binds to) all of the amino acid residues shown inTable 7.

TABLE 7 Exemplary Human APRIL Amino Acid Residues that Bind toAnti-APRIL Antibodies (amino acid numbering based on SEQ ID NO: 85)Amino Acid Position Amino Acid 132 Asp 170 Leu 175 Thr 176 Phe 177 Thr178 Met 181 Val 192 Thr 195 Arg 197 Ile 205 Asp 206 Arg 208 Tyr 228 Iso230 Pro 231 Arg 232 Ala 241 His

In an embodiment, the antibody molecule, e.g., an anti-APRIL antibodymolecule having one, two, three, four, five or six CDRs of any ofmonoclonal antibodies 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1210, 2419-1305,2419-1306, 2419-1310, or 2419-1406, binds to one or more amino acidsdescribed in Table 7. In another embodiment, the antibody molecule,e.g., a human-specific, anti-APRIL antibody molecule, e.g., having one,two, three, four, five or six CDRs of any of monoclonal antibodies 2419,2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, binds to mouse APRIL when one or more (e.g., 2, 3, 4 or all)following positions within mouse APRIL (mouse APRIL numbering applies)are mutated, e.g., to the following: A120D, N224R, H163Q, K219I, orR181Q. In yet another embodiment, the antibody molecule, e.g., ahuman-specific, anti-APRIL antibody molecule, e.g., having one, two,three, four, five or six CDRs of any of monoclonal antibodies 2419,2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805,2419-0806, 2419-1204, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, binds to mouse APRIL when the lysine at position 219 (mouseAPRIL numbering applies) is mutated, e.g., to an isoleucine (i.e.,K219I).

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, or all) of the amino acid residues of human APRIL shownin Table 6. In an embodiment, the antibody molecule is an antibodymolecule described herein, e.g., monoclonal antibody 2218, 2419, 2621,2622, 3125, 3327, 3525, 3530, 4035, 3934, 3833, 3631, 3732, 4338, 4540,or 4237.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, orall) of the amino acid residues of human APRIL chosen from D132, V174,F176, V181, Q190, R195, R206, Y208, 1228, or N237. In an embodiment, theantibody molecule contacts (e.g., binds or substantially binds to) oneor more (e.g., 2, 3, 4, 5, or all) of the amino acid residues of humanAPRIL chosen from V174, F176, Q190, R195, R206, or Y208. In anembodiment, the antibody molecule contacts (e.g., binds or substantiallybinds to) one or more (e.g., 2, 3, or all) of the amino acid residues ofhuman APRIL chosen from F176, V181, Q190, or 1228. In an embodiment, theantibody molecule contacts (e.g., binds or substantially binds to) oneor more (e.g., 2, or all) of the amino acid residues of human APRILchosen from V174, R206, or Y208.

In an embodiment, the antibody molecule does not contact (e.g., does notbind or does not substantially bind to) at least one (e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) of theamino acid residues of human APRIL shown in Table 6. In an embodiment,the antibody molecule is an antibody molecule described herein, e.g.,monoclonal antibody 2218, 2419, 2621, 2622, 3125, 3327, 3525, 3530,4035, 3934, 3833, 3631, 3732, 4338, 4540, or 4237.

In an embodiment, the antibody molecule does not contact (e.g., does notbind or does not substantially bind to) one or more (e.g., 2, 3, 4, 5,6, or all) of the amino acid residues of human APRIL chosen from F176,V181, Q190, S226, 1228, Y208, or N237. In an embodiment, the antibodymolecule does not contact (e.g., does not bind or does not substantiallybind to) one or more (e.g., 2, 3, or all) of the amino acid residues ofhuman APRIL chosen from V181, 5226, 1228, or N237. In an embodiment, theantibody molecule does not contact (e.g., does not bind or does notsubstantially bind to) one or both of the amino acid residues of humanAPRIL chosen from Y208 or N237. In an embodiment, the antibody moleculedoes not contact (e.g., does not bind or does not substantially bind to)one or more (e.g., 2, 3, or all) of the amino acid residues of humanAPRIL chosen from F176, V181, Q190, or N237.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, or all) of theamino acid residues of human APRIL chosen from V174, F176, Q190, R195,R206, or Y208; and does not contact (e.g., does not bind or does notsubstantially bind to) one or more (e.g., 2, 3, or all) of the aminoacid residues of human APRIL chosen from V181, S226, 1228, or N237. Inan embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or both of the amino acid residues of humanAPRIL chosen from V174 or R206; and does not contact (e.g., does notbind or does not substantially bind to) one or both of the amino acidresidues of human APRIL chosen from V181 or N237 (and optionally S226).In an embodiment, the antibody molecule comprises one or more (e.g., twoor three) heavy chain CDRs, one or more (e.g., two or three) light chainCDRs, or both of monoclonal antibody 4035. In an embodiment, theantibody molecule comprises a heavy chain region, a light chain variableregion, or both, of monoclonal antibody 4035. In an embodiment,monoclonal antibody 4035 is a humanized antibody molecule.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, or all) of the aminoacid residues of human APRIL chosen from F176, V181, Q190, or 1228; anddoes not contact (e.g., does not bind or does not substantially bind to)one or both of the amino acid residues of human APRIL chosen from Y208or N237. In an embodiment, the antibody molecule contacts (e.g., bindsor substantially binds to) amino acid residue 1228 of human APRIL; anddoes not contact (e.g., does not bind or does not substantially bind to)one or both of the amino acid residues of human APRIL chosen from Y208or N237. In an embodiment, the antibody molecule comprises one or more(e.g., two or three) heavy chain CDRs, one or more (e.g., two or three)light chain CDRs, or both of monoclonal antibody 2419. In an embodiment,the antibody molecule comprises a heavy chain region, a light chainvariable region, or both, of monoclonal antibody 2419. In an embodiment,monoclonal antibody 2419 is a humanized antibody molecule.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, or all) of the amino acidresidues of human APRIL chosen from V174, R206, or Y208; and does notcontact (e.g., does not bind or does not substantially bind to) one ormore (e.g., 2, 3, or all) of the amino acid residues of human APRILchosen from F176, V181, Q190, or N237. In an embodiment, the antibodymolecule contacts (e.g., binds or substantially binds to) one or both ofthe amino acid residues of human APRIL chosen from V174 or R206; anddoes not contact (e.g., does not bind or does not substantially bind to)one or more (e.g., 2, 3, or all) of the amino acid residues of humanAPRIL chosen from F176, V181, Q190, or N237. In an embodiment, theantibody molecule comprises one or more (e.g., two or three) heavy chainCDRs, one or more (e.g., two or three) light chain CDRs, or both ofmonoclonal antibody 3833. In an embodiment, the antibody moleculecomprises a heavy chain region, a light chain variable region, or both,of monoclonal antibody 3833. In an embodiment, monoclonal antibody 3833is a humanized antibody molecule.

In an embodiment, the epitope overlaps with a CRD2 receptor bindingsite. In an embodiment, the epitope is non-linear epitope, e.g., thatspans across a monomer interface. In an embodiment, the epitope is in aregion associated with both TACI and BCMA receptor blocking.

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, or all) of the amino acid residues of human APRILchosen from V133, V181, E185, Q187, G188, R189, Q190, E191, T192, R195,H218, L219, H220, 5226, 1228, P230 (located in monomer A). In anembodiment, the antibody molecule contacts (e.g., binds or substantiallybinds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) of theamino acid residues of human APRIL chosen from V121, 1123, Q139, P140,A141, L142, N237, 5239, P240, or H241 (located in monomer B). In anembodiment, the antibody molecule contacts (e.g., binds or substantiallybinds to) one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all) of the amino acidresidues of human APRIL chosen from V133, V181, E185, Q187, G188, R189,Q190, E191, T192, R195, H218, L219, H220, 5226, 1228, P230 (located inmonomer A); V121, 1123, Q139, P140, A141, L142, N237, 5239, P240, orH241 (located in monomer B).

In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, or all) of the aminoacid residues of human APRIL chosen from V181, Q190, T192, and 1228(located in monomer A). In an embodiment, the antibody molecule contacts(e.g., binds or substantially binds to) one or both of the amino acidresidues of human APRIL chosen from A141 or H241 (located in monomer B).In an embodiment, the antibody molecule contacts (e.g., binds orsubstantially binds to) one or more (e.g., 2, 3, 4, 5, or all) of theamino acid residues of human APRIL chosen from V181, Q190, T192, and1228 (located in monomer A); A141 or H241 (located in monomer B).

In an embodiment, the antibody molecule comprises one or more (e.g., twoor three) heavy chain CDRs, one or more (e.g., two or three) light chainCDRs, or both of monoclonal antibody 2419. In an embodiment, theantibody molecule comprises a heavy chain region, a light chain variableregion, or both, of monoclonal antibody 2419. In an embodiment,monoclonal antibody 2419 is a humanized antibody molecule.

In an embodiment, the epitope comprise one or more (e.g., 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,or all) of the amino acid residues of human APRIL chosen from V133,V181, E185, Q187, G188, R189, Q190, E191, T192, R195, H218, L219, H220,S226, 1228, P230 (located in monomer A); V121, 1123, Q139, P140, A141,L142, N237, 5239, P240, or H241 (located in monomer B). In anembodiment, the epitope comprises one or more (e.g., 2, 3, 4, 5, or all)of the amino acid residues of human APRIL chosen from V181, Q190, T192,and 1228 (located in monomer A); A141 or H241 (located in monomer B).

In an embodiment, a structural representation of this epitope isdepicted in FIG. 38B. In an embodiment, the epitope comprises one ormore (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, or all) of the amino acid residues shown inTable 8.

In an embodiment, the antibody molecule contacts (e.g., binds, orsubstantially binds, to) all of the amino acid residues shown in any ofTables 3-4 or 7-8. In an embodiment, the epitope comprises, or consistsof, all of the amino acid residues shown in any of Tables 3-4 or 7-8.

In an embodiment, the antibody molecule has one or more of the followingproperties described herein, e.g., one or more (e.g., two, three or all)of: (i) binds, or substantially binds, to human APRIL; (ii) binds, orsubstantially binds, to mouse APRIL; (iii) inhibits, or substantiallyinhibits, binding of APRIL (e.g., human APRIL, mouse APRIL, or both) toTACI (e.g., human TACI, mouse TACI, or both); or (iv) inhibits, orsubstantially inhibits, binding of APRIL (e.g., human APRIL, mouseAPRIL, or both) to BCMA (e.g., human BCMA, mouse BCMA, or both). In anembodiment, the antibody molecule binds, or substantially binds, tomouse APRIL. In another embodiment, the antibody molecule does not bind,or binds with low affinity, to mouse APRIL.

Antibody Molecules

Disclosed herein are antibody molecules that bind to APRIL, e.g., anAPRIL molecule described herein.

As used herein, the term “antibody molecule” refers to a protein, e.g.,an immunoglobulin chain or a fragment thereof, comprising at least oneimmunoglobulin variable domain sequence. The term “antibody molecule”includes, for example, full-length, mature antibodies andantigen-binding fragments of an antibody. For example, an antibodymolecule can include a heavy (H) chain variable domain sequence(abbreviated herein as VH), and a light (L) chain variable domainsequence (abbreviated herein as VL). In another example, an antibodymolecule includes two heavy (H) chain variable domain sequences and twolight (L) chain variable domain sequence, thereby forming two antigenbinding sites, such as Fab, Fab′, F(ab′)2, Fc, Fd, Fd′, Fv, single chainantibodies (scFv for example), single variable domain antibodies,diabodies (Dab) (bivalent and bispecific), and chimeric (e.g.,humanized) antibodies, which may be produced by the modification ofwhole antibodies or those synthesized de novo using recombinant DNAtechnologies. These functional antibody fragments retain the ability toselectively bind with their respective antigen or receptor. Antibodiesand antibody fragments can be from any class of antibodies including,but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass(e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. The antibody moleculescan be monoclonal or polyclonal. The antibody molecule can also be ahuman, humanized, CDR-grafted, or in vitro generated antibody. Theantibody molecule can have a heavy chain constant region chosen from,e.g., IgG1, IgG2, IgG3, or IgG4. The antibody molecule can also have alight chain chosen from, e.g., kappa or lambda. The term“immunoglobulin” (Ig) is used interchangeably with the term “antibody”herein.

Examples of antigen-binding fragments include: (i) a Fab fragment, amonovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) aF(ab′)2 fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; (iii) a Fd fragmentconsisting of the VH and CH1 domains; (iv) a Fv fragment consisting ofthe VL and VH domains of a single arm of an antibody, (v) a diabody(dAb) fragment, which consists of a VH domain; (vi) a camelid orcamelized variable domain; (vii) a single chain Fv (scFv), see e.g.,Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc.Natl. Acad. Sci. USA 85:5879-5883); (viii) a single domain antibody.These antibody fragments may be obtained using any suitable method,including several conventional techniques known to those with skill inthe art, and the fragments can be screened for utility in the samemanner as are intact antibodies.

The term “antibody” includes intact molecules as well as functionalfragments thereof. Constant regions of the antibodies can be altered,e.g., mutated, to modify the properties of the antibody (e.g., toincrease or decrease one or more of: Fc receptor binding, antibodyglycosylation, the number of cysteine residues, effector cell function,or complement function).

The antibody molecule can be a single chain antibody. A single-chainantibody (scFv) may be engineered (see, for example, Colcher, D. et al.(1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin CancerRes 2:245-52). The single chain antibody can be dimerized ormultimerized to generate multivalent antibodies having specificities fordifferent epitopes of the same target protein.

The antibody molecules disclosed herein can also be single domainantibodies. Single domain antibodies can include antibodies whosecomplementary determining regions are part of a single domainpolypeptide. Examples include, but are not limited to, heavy chainantibodies, antibodies naturally devoid of light chains, single domainantibodies derived from conventional 4-chain antibodies, engineeredantibodies and single domain scaffolds other than those derived fromantibodies. Single domain antibodies may be any of the art, or anyfuture single domain antibodies. Single domain antibodies may be derivedfrom any species including, but not limited to mouse, human, camel,llama, fish, shark, goat, rabbit, and bovine. According to some aspects,a single domain antibody is a naturally occurring single domain antibodyknown as heavy chain antibody devoid of light chains. Such single domainantibodies are disclosed in WO 94/04678, for example. For clarityreasons, this variable domain derived from a heavy chain antibodynaturally devoid of light chain is known herein as a VHH or nanobody todistinguish it from the conventional VH of four chain immunoglobulins.Such a VHH molecule can be derived from antibodies raised in Camelidaespecies, for example in camel, llama, dromedary, alpaca and guanaco.Other species besides Camelidae may produce heavy chain antibodiesnaturally devoid of light chain; such VHHs are also contemplated.

The VH and VL regions can be subdivided into regions ofhypervariability, termed “complementarity determining regions” (CDR),interspersed with regions that are more conserved, termed “frameworkregions” (FR or FW). The terms “complementarity determining region,” and“CDR,” as used herein refer to the sequences of amino acids withinantibody variable regions which confer antigen specificity and bindingaffinity. As used herein, the terms “framework,” “FW” and “FR” are usedinterchangeably.

The extent of the framework region and CDRs has been precisely definedby a number of methods (see, Kabat, E. A., et al. (1991) Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242; Chothia, C. etal. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used byOxford Molecular's AbM antibody modeling software. See, generally, e.g.,Protein Sequence and Structure Analysis of Antibody Variable Domains.In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R.,Springer-Verlag, Heidelberg). In an embodiment, the followingdefinitions are used: AbM definition of CDR1 of the heavy chain variabledomain and Kabat definitions for the other CDRs. In an embodiment, Kabatdefinitions are used for all CDRs. In addition, embodiments describedwith respect to Kabat or AbM CDRs may also be implemented using Chothiahypervariable loops. Each VH and VL typically includes three CDRs andfour FRs, arranged from amino-terminus to carboxy-terminus in thefollowing order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

As used herein, an “immunoglobulin variable domain sequence” refers toan amino acid sequence which can form the structure of an immunoglobulinvariable domain. For example, the sequence may include all or part ofthe amino acid sequence of a naturally-occurring variable domain. Forexample, the sequence may or may not include one, two, or more N- orC-terminal amino acids, or may include other alterations that arecompatible with formation of the protein structure.

The term “antigen-binding region” refers to the part of an antibodymolecule that comprises determinants that form an interface that bindsto an antigen, e.g., APRIL, or an epitope thereof. With respect toproteins (or protein mimetics), the antigen-binding region typicallyincludes one or more loops (of at least, e.g., four amino acids or aminoacid mimics) that form an interface that binds to the antigen, e.g.,APRIL. Typically, the antigen-binding region of an antibody moleculeincludes at least one or two CDRs and/or hypervariable loops, or moretypically at least three, four, five or six CDRs and/or hypervariableloops.

The terms “compete” or “cross-compete” are used interchangeably hereinto refer to the ability of an antibody molecule to interfere withbinding of an anti-APRIL antibody molecule, e.g., an anti-APRIL antibodymolecule provided herein, to a target, e.g., APRIL. The interferencewith binding can be direct or indirect (e.g., through an allostericmodulation of the antibody molecule or the target). The extent to whichan antibody molecule is able to interfere with the binding of anotherantibody molecule to the target, and therefore whether it can be said tocompete, can be determined using a competition binding assay, forexample, a FACS assay, an ELISA or BIACORE assay. In an embodiment, acompetition binding assay is a quantitative competition assay. In anembodiment, a first anti-APRIL antibody molecule is said to compete forbinding to the target with a second anti-APRIL antibody molecule whenthe binding of the first antibody molecule to the target is reduced by10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more,55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% ormore, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more ina competition binding assay (e.g., a competition assay describedherein).

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope. Amonoclonal antibody can be made by hybridoma technology or by methodsthat do not use hybridoma technology (e.g., recombinant methods).

An “effectively human” protein is a protein that does not evoke aneutralizing antibody response, e.g., the human anti-murine antibody(HAMA) response. HAMA can be problematic in a number of circumstances,e.g., if the antibody molecule is administered repeatedly, e.g., intreatment of a chronic or recurrent disease condition. A HAMA responsecan make repeated antibody administration potentially ineffectivebecause of an increased antibody clearance from the serum (see, e.g.,Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and alsobecause of potential allergic reactions (see, e.g., LoBuglio et al.,Hybridoma, 5:5117-5123 (1986)).

The antibody molecule can be a polyclonal or a monoclonal antibody. Insome embodiments, the antibody can be recombinantly produced, e.g.,produced by any suitable phage display or combinatorial methods.

Various phage display and combinatorial methods for generatingantibodies are known in the art (as described in, e.g., Ladner et al.U.S. Pat. No. 5,223,409; Kang et al. International Publication No. WO92/18619; Dower et al. International Publication No. WO 91/17271; Winteret al. International Publication WO 92/20791; Markland et al.International Publication No. WO 92/15679; Breitling et al.International Publication WO 93/01288; McCafferty et al. InternationalPublication No. WO 92/01047; Garrard et al. International PublicationNo. WO 92/09690; Ladner et al. International Publication No. WO90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al.(1992) Hum Antibod Hybridomas 3:81-85; Huse et al. (1989) Science246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al.(1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991)Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982, the contentsof all of which are incorporated by reference herein).

In an embodiment, the antibody molecule is a fully human antibody (e.g.,an antibody made in a mouse which has been genetically engineered toproduce an antibody from a human immunoglobulin sequence), or anon-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g.,monkey), camel antibody. In an embodiment, the non-human antibody is arodent (mouse or rat antibody). Methods of producing rodent antibodiesare known in the art.

Human monoclonal antibodies can be generated using transgenic micecarrying the human immunoglobulin genes rather than the mouse system.Splenocytes from these transgenic mice immunized with the antigen ofinterest are used to produce hybridomas that secrete human mAbs withspecific affinities for epitopes from a human protein (see e.g., Wood etal. International Application WO 91/00906, Kucherlapati et al. PCTpublication WO 91/10741; Lonberg et al. International Application WO92/03918; Kay et al. International Application 92/03917; Lonberg, N. etal. 1994 Nature 368:856-859; Green, L. L. et al. 1994 Nature Genet.7:13-21; Morrison, S. L. et al. 1994 Proc. Natl. Acad. Sci. USA81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon etal. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol21:1323-1326).

An antibody can be one in which the variable region, or a portionthereof, e.g., the CDRs, are generated in a non-human organism, e.g., arat or mouse. Chimeric, CDR-grafted, and humanized antibodies are withinthe invention. Antibodies generated in a non-human organism, e.g., a rator mouse, and then modified, e.g., in the variable framework or constantregion, to decrease antigenicity in a human are within the invention.

Chimeric antibodies can be produced by any suitable recombinant DNAtechnique. Several are known in the art (see Robinson et al.,International Patent Application Publication No. WO1987/002671; Akira,et al., European Patent Application Publication No. 184,187; Taniguchi,M., European Patent Application Publication No. 171,496; Morrison etal., European Patent Application Publication No. 173,494; Neuberger etal., International Patent Application Publication No. WO 86/01533;Cabilly et al. U.S. Pat. No. 4,816,567; Cabilly et al., European PatentApplication Publication No. 125,023; Better et al. (1988 Science240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987,J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimuraet al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

A humanized or CDR-grafted antibody will have at least one or two butgenerally all three recipient CDRs (of heavy and or light immunoglobulinchains) replaced with a donor CDR. The antibody may be replaced with atleast a portion of a non-human CDR or only some of the CDRs may bereplaced with non-human CDRs. It is only necessary to replace the numberof CDRs required for binding of the humanized antibody tolipopolysaccharide. In an embodiment, the donor will be a rodentantibody, e.g., a rat or mouse antibody, and the recipient will be ahuman framework or a human consensus framework. Typically, theimmunoglobulin providing the CDRs is called the “donor” and theimmunoglobulin providing the framework is called the “acceptor.” In someembodiments, the donor immunoglobulin is a non-human (e.g., rodent). Theacceptor framework is typically a naturally-occurring (e.g., a human)framework or a consensus framework, or a sequence about 85% or higher,e.g., 90%, 95%, 99% or higher identical thereto.

As used herein, the term “consensus sequence” refers to the sequenceformed from the most frequently occurring amino acids (or nucleotides)in a family of related sequences (See e.g., Winnaker, From Genes toClones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family ofproteins, each position in the consensus sequence is occupied by theamino acid occurring most frequently at that position in the family. Iftwo amino acids occur equally frequently, either can be included in theconsensus sequence. A “consensus framework” refers to the frameworkregion in the consensus immunoglobulin sequence.

An antibody can be humanized by any suitable method, and several suchmethods known in the art (see e.g., Morrison, S. L., 1985, Science229:1202-1207, by Oi et al., 1986, BioTechniques 4:214, and by Queen etal. U.S. Pat. Nos. 5,585,089, 5,693,761 and 5,693,762, the contents ofall of which are hereby incorporated by reference).

Humanized or CDR-grafted antibodies can be produced by CDR-grafting orCDR substitution, wherein one, two, or all CDRs of an immunoglobulinchain can be replaced. See e.g., U.S. Pat. No. 5,225,539; Jones et al.1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidleret al. 1988 J. Immunol. 141:4053-4060; Winter U.S. Pat. No. 5,225,539,the contents of all of which are hereby expressly incorporated byreference. Winter describes a CDR-grafting method which may be used toprepare humanized antibodies (UK Patent Application GB 2188638A, filedon Mar. 26, 1987; Winter U.S. Pat. No. 5,225,539), the contents of whichis expressly incorporated by reference.

Also provided are humanized antibodies in which specific amino acidshave been substituted, deleted or added. Criteria for selecting aminoacids from the donor are described in, e.g., U.S. Pat. No. 5,585,089,e.g., columns 12-16 of U.S. Pat. No. 5,585,089, the contents of whichare hereby incorporated by reference. Other techniques for humanizingantibodies are described in Padlan et al. EP 519596 A1, published onDec. 23, 1992.

In an embodiment, the antibody molecule has a heavy chain constantregion chosen from, e.g., the heavy chain constant regions of IgG1, IgG2(e.g., IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly,chosen from, e.g., the (e.g., human) heavy chain constant regions ofIgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody moleculehas a light chain constant region chosen from, e.g., the (e.g., human)light chain constant regions of kappa or lambda. The constant region canbe altered, e.g., mutated, to modify the properties of the antibodymolecule (e.g., to increase or decrease one or more of: Fc receptorbinding, antibody glycosylation, the number of cysteine residues,effector cell function, and/or complement function). In an embodiment,the antibody molecule has effector function and can fix complement. Inanother embodiment, the antibody molecule does not recruit effectorcells or fix complement. In certain embodiments, the antibody moleculehas reduced or no ability to bind an Fc receptor. For example, it may bean isotype or subtype, fragment or other mutant, which does not supportbinding to an Fc receptor, e.g., it has a mutagenized or deleted Fcreceptor binding region.

In an embodiment, a constant region of the antibody molecule is altered.Methods for altering an antibody constant region are known in the art.Antibody molecules s with altered function, e.g. altered affinity for aneffector ligand, such as FcR on a cell, or the C1 component ofcomplement can be produced by replacing at least one amino acid residuein the constant portion of the antibody with a different residue (seee.g., EP 388,151 A1, U.S. Pat. Nos. 5,624,821 and 5,648,260, thecontents of all of which are hereby incorporated by reference) Aminoacid mutations which stabilize antibody structure, such as S228P (EUnomenclature, S241P in Kabat nomenclature) in human IgG4 are alsocontemplated. Similar type of alterations could be described which ifapplied to the murine, or other species immunoglobulin would reduce oreliminate these functions.

In an embodiment, the only amino acids in the antibody molecule arecanonical amino acids. In an embodiment, the antibody molecule comprisesnaturally-occurring amino acids; analogs, derivatives and congenersthereof; amino acid analogs having variant side chains; and/or allstereoisomers of any of any of the foregoing. The antibody molecule maycomprise the D- or L-optical isomers of amino acids and peptidomimetics.

A polypeptide of an antibody molecule described herein may be linear orbranched, it may comprise modified amino acids, and it may beinterrupted by non-amino acids. The antibody molecule may also bemodified; for example, by disulfide bond formation, glycosylation,lipidation, acetylation, phosphorylation, or any other manipulation,such as conjugation with a labeling component. The polypeptide can beisolated from natural sources, can be a produced by recombinanttechniques from a eukaryotic or prokaryotic host, or can be a product ofsynthetic procedures.

The antibody molecule described herein can be used alone in unconjugatedform, or can be bound to a substance, e.g., a toxin or moiety (e.g., atherapeutic drug; a compound emitting radiation; molecules of plant,fungal, or bacterial origin; or a biological protein (e.g., a proteintoxin) or particle (e.g., a recombinant viral particle, e.g., via aviral coat protein). For example, the anti-APRIL antibody can be coupledto a radioactive isotope such as an α-, β-, or γ-emitter, or a β- andγ-emitter.

An antibody molecule can be derivatized or linked to another functionalmolecule (e.g., another peptide or protein). As used herein, a“derivatized” antibody molecule is one that has been modified. Methodsof derivatization include but are not limited to the addition of afluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinityligand such as biotin. Accordingly, the antibody molecules are intendedto include derivatized and otherwise modified forms of the antibodiesdescribed herein, including immunoadhesion molecules. For example, anantibody molecule can be functionally linked (by chemical coupling,genetic fusion, noncovalent association or otherwise) to one or moreother molecular entities, such as another antibody (e.g., a bispecificantibody or a diabody), a detectable agent, a toxin, a pharmaceuticalagent, and/or a protein or peptide that can mediate association of theantibody or antibody portion with another molecule (such as astreptavidin core region or a polyhistidine tag).

Some types of derivatized antibody molecule are produced by crosslinkingtwo or more antibodies (of the same type or of different types, e.g., tocreate bispecific antibodies). Suitable crosslinkers include those thatare heterobifunctional, having two distinctly reactive groups separatedby an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimideester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkersare available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents with which an anti-dengue antibody molecule maybe derivatized (or labeled) to include fluorescent compounds, variousenzymes, prosthetic groups, luminescent materials, bioluminescentmaterials, fluorescent emitting metal atoms, e.g., europium (Eu), andother anthanides, and radioactive materials (described below). Exemplaryfluorescent detectable agents include fluorescein, fluoresceinisothiocyanate, rhodamine, 5dimethylamine-1-napthalenesulfonyl chloride,phycoerythrin and the like. An antibody may also be derivatized withdetectable enzymes, such as alkaline phosphatase, horseradishperoxidase, β-galactosidase, acetylcholinesterase, glucose oxidase andthe like. When an antibody is derivatized with a detectable enzyme, itis detected by adding additional reagents that the enzyme uses toproduce a detectable reaction product. For example, when the detectableagent horseradish peroxidase is present, the addition of hydrogenperoxide and diaminobenzidine leads to a colored reaction product, whichis detectable. An antibody molecule may also be derivatized with aprosthetic group (e.g., streptavidin/biotin and avidin/biotin). Forexample, an antibody may be derivatized with biotin, and detectedthrough indirect measurement of avidin or streptavidin binding. Examplesof suitable fluorescent materials include umbelliferone, fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; an example of aluminescent material includes luminol; and examples of bioluminescentmaterials include luciferase, luciferin, and aequorin.

Labeled antibody molecules can be used, for example, diagnosticallyand/or experimentally in a number of contexts, including (i) to isolatea predetermined antigen by standard techniques, such as affinitychromatography or immunoprecipitation; (ii) to detect a predeterminedantigen (e.g., in a cellular lysate or cell supernatant) in order toevaluate the abundance and pattern of expression of the protein; (iii)to monitor protein levels in tissue as part of a clinical testingprocedure, e.g., to determine the efficacy of a given treatment regimen.

An antibody molecule may be conjugated to another molecular entity,typically a label or a therapeutic (e.g., antimicrobial (e.g.,antibacterial or bactericidal), immunomodulatory, immunostimulatory,cytotoxic, or cytostatic) agent or moiety. Radioactive isotopes can beused in diagnostic or therapeutic applications. Radioactive isotopesthat can be coupled to the antibody molecules include, but are notlimited to α-, β-, or γ-emitters, or β- and γ-emitters. Such radioactiveisotopes include, but are not limited to iodine (¹³¹I or ¹²⁵I), yttrium(⁹⁰Y), lutetium (¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine(²¹¹At) rhenium (¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), indium (¹¹¹In),technetium (⁹⁹ mTc), phosphorus (³²P), rhodium (¹⁸⁸Rh), sulfur (³⁵S),carbon (¹⁴C), tritium (³H), chromium (⁵¹Cr), chlorine (³⁶Cl), cobalt(⁵⁷Co or ⁵⁸Co), iron (⁵⁹Fe), selenium (⁷⁵Se), or gallium (⁶⁷Ga).Radioisotopes useful as therapeutic agents include yttrium (⁹⁰Y),lutetium (¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine (²¹¹At),rhenium (¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), and rhodium (¹⁸⁸Rh).Radioisotopes useful as labels, e.g., for use in diagnostics, includeiodine (¹³¹I or ¹²⁵I), indium (¹¹¹In), technetium (⁹⁹mTc), phosphorus(³²P), carbon (¹⁴C), and tritium (³H), or one or more of the therapeuticisotopes listed above.

The present disclosure provides radiolabeled antibody molecules andmethods of labeling the same. In an embodiment, a method of labeling anantibody molecule is disclosed. The method includes contacting anantibody molecule, with a chelating agent, to thereby produce aconjugated antibody. The conjugated antibody is radiolabeled with aradioisotope, e.g., ¹¹¹Indium, ⁹⁰Yttrium and ¹⁷⁷Lutetium, to therebyproduce a labeled antibody molecule.

In some aspects, this disclosure provides a method of making an antibodymolecule disclosed herein. The method includes: providing an antigen,e.g., APRIL or a fragment thereof; obtaining an antibody molecule thatspecifically binds to the antigen; evaluating efficacy of the antibodymolecule in modulating activity of the antigen and/or organismexpressing the antigen, e.g., APRIL. The method can further includeadministering the antibody molecule, including a derivative thereof(e.g., a humanized antibody molecule) to a subject, e.g., a human.

This disclosure provides an isolated nucleic acid molecule encoding theabove antibody molecule, vectors and host cells thereof. The nucleicacid molecule includes, but is not limited to, RNA, genomic DNA andcDNA.

Amino acid and nucleotide sequences of exemplary antibody molecules aredescribed in Tables 1 and 2, respectively. Amino acid sequences ofadditional exemplary humanized antibody molecules are described in Table5.

TABLE 1The amino acid sequences of the heavy chain variable region (VH) and light chain variable region (VL) of the exemplary anti-APRIL antibodiesare provided as follows. CDRs, defined according to the Kabat system, are underlined and bold, while CDRs defined according to theChothia system are italicized. SEQ ID SEQ ID SEQ ID  Antibody ChainAmino Acid Sequence NO Chothia CDR NO Kabat CDR NO 2218 VHDVQLQESGPGLVKPSQSLSLTCSVTGYSIT

YW   9 HCDR1 GYSITSGY   1 HCDR1 SGYYWN   7 N WIRQFPGNKLEWMG YI

NNYNPSLKN RISI HCDR2 SYDGY   2 HCDR2 YISYDGYNNYNPSLKN   8TRDTSKNQFFLKLNSVTTEDTATYYCAN

HCDR3 YYDYEDWYFGV   3 HCDR3 YYDYEDWYFGV   3

WGTGTTVTVSS VL DIVLTQSPASLAMSLGKRATISC

   10 LCDR1 RASESVSIIGTNSIH   4 LCDR1 RASESVSIIGTNSIH   4

WYQQKPGQPPKLLIY

GVPARFSGSG LCDR2 HASNLET   5 LCDR2 HASNLET   5 SRTDFTLTIDPVEEDDVAIYYC

FGGG LCDR3 LQSRKIPYT   6 LCDR3 LQSRKIPYT   6 TKLEIK 2419 VHQVQLQQSGAELVKPGASVRLSCEASGYTFT

TIH  19 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVKQRSGQGLEWIG WI

INYNEKFKD KATL HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYNEKFKD  18TADKSSSTVYLELGRLTSKDSAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTTLTVSS VL NIVMTQSPASLAVSLGQRATISC

 20 LCDR1 RASESVDNDGIRFMH  14 LCDR1 RASESVDNDGIRFMH  14

WYQQKPGQPPKLLIY

GIPARFSGSG LCDR2 RASNLES  15 LCDR2 RASNLES  15 SRTDFTLTINPVETDDVATYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKLELK 2419-1305 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 283 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSISTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1306 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 283 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSISTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

286 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTRAT 285 LCDR2 RASTRAT 285 SRTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1310 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 283 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSISTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL DIVMTQSPDSLAVSLGERATINC

316 LCDR1 KSSQSVDNDGIRFLH 314 LCDR1 KSSQSVDNDGIRFLH 314

WYQQKPGQPPKLLIY

GVPDRFSGSG LCDR2 RASTRES 315 LCDR2 RASTRES 315 SGTDFTLTISSLQAEDVAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0806 VHEVQLVQSGAEVKKPGESLKISCKASGYTFT

TIH 288 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQMPGKGLEWMG WI

INYSPSFQG QVTI HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYSPSFQG 287SADKSISTVYLQWSSLKASDTAMYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

286 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTRAT 285 LCDR2 RASTRAT 285 SRTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0205 VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFT

TIH 289 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQAPGQGLEWMG WI

INYAQKFQG RVTI HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TADKSTSTAYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0406 VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFT

TIH 291 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQAPGQGLEWMG WI

INYAEKFKG RVTL HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAEKFKG 290TADKSTSTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

286 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTRAT 285 LCDR2 RASTRAT 285 SRTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0605 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 317 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQAPGQGLEWMG WI

INYAQKFQG RVTL HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TADKSTSTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0805 VHEVQLVQSGAEVKKPGESLKISCKASGYTFT

TIH 288 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQMPGKGLEWMG WI

INYSPSFQG QVTI HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYSPSFQG 287SADKSISTVYLQWSSLKASDTAMYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYY

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0105 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 292 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQAPGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TADKSISTVYMELSRLRSDDTAVYYCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1204 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 294 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSSSTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

295 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTLET 293 LCDR2 RASTLET 293 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1205 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 294 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSSSTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

284 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASNRET 281 LCDR2 RASNRET 281 SGTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1210 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 294 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TANKSSSTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL DIVMTQSPDSLAVSLGERATINC

316 LCDR1 KSSQSVDNDGIRFLH 314 LCDR1 KSSQSVDNDGIRFLH 314

WYQQKPGQPPKLLIY

GVPDRFSGSG LCDR2 RASTRES 315 LCDR2 RASTRES 315 SGTDFTLTISSLQAEDVAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-1406 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFT

TIH 296 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQATGQGLEWMG WI

INYAQKFQG RVTM HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TADKSISTVYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

286 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTRAT 285 LCDR2 RASTRAT 285 SRTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2419-0206 VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFT

TIH 289 HCDR1 GYTFTDY  11 HCDR1 DYTIH  17 WVRQAPGQGLEWMG WI

INYAQKFQG RVTI HCDR2 YPLRGS  12 HCDR2 WIYPLRGSINYAQKFQG 282TADKSTSTAYMELSSLRSEDTAVYFCAR

HCDR3 HGAYYSNAFDY  13 HCDR3 HGAYYSNAFDY  13

WGQGTLVTVSS VL EIVMTQSPATLSVSPGERATLSC

286 LCDR1 RASESVDNDGIRFLH 280 LCDR1 RASESVDNDGIRFLH 280

WYQQKPGQAPRLLIY

GIPARFSGSG LCDR2 RASTRAT 285 LCDR2 RASTRAT 285 SRTEFTLTISSLQSEDFAVYYC

FGGG LCDR3 QQSNKDPYT  16 LCDR3 QQSNKDPYT  16 TKVEIK 2621 VHEVQLQQSGAELVRPGSSVKMSCKTSGYTFT

GIN  29 HCDR1 GYTFTSY  21 HCDR1 SYGIN  27 WVKQRPGQGLEWIG YI

AEYNERFKG KATL HCDR2 YIGNGY  22 HCDR2 YIYIGNGYAEYNERFKG  28TSDTSSSTAYMQLSSLTSEDSAIYFCAL

HCDR3 YYPWFTY  23 HCDR3 YYPWFTY  23 WGQGTLVTVSA VLDIQMTQSPASLSASVGDSVTITC

W  30 LCDR1 RASENIYSYLA  24 LCDR1 RASENIYSYLA  24 YQQKQGKSPQLLVY

GVPSRFSGSGSGTQ LCDR2 NAKTLAE  25 LCDR2 NAKTLAE  25 FSLKINSLQPEDFGNYYC

FGGGTKLE LCDR3 QHHYDTPFT  26 LCDR3 QHHYDTPFT  26 IK 2922 VHQVQLHQSGPELVKPGASVKLSCKTSGYTFT

DVF  39 HCDR1 GYTFTSY  21 HCDR1 SYDVF  37 WVKQRPGQGLEWIG WI

STKYNEKFKG KATL HCDR2 YPRDSS  32 HCDR2 WIYPROSSTKYNEKFKG  38TVDTSSSTAYMELHSLTSEDSAVYFCAK

HCDR3 EGYDYDKRGFDY  33 HCDR3 EGYDYDKRGFDY  33

WGQGTTLTVSS VL DIVLTQSPASLAVSLGQRAIISC

 40 LCDR1 KASQSVSFAGTNLMH  34 LCDR1 KASQSVSFAGTNLMH  34

WYQQRPGQQPKLLIY

GVPTRFSGSG LCDR2 RASNLEP  35 LCDR2 RASNLEP  35 SRTDFTLNIHPVEEDDAATYYC

FGGG LCDR3 QQSREYPWT  36 LCDR3 QQSREYPWT  36 TKLEIK 3125 VHQVQLQQSGAELVRPGASVTLSCKASGYTFT

EMH  49 HCDR1 GYTFTDY  11 HCDR1 DYEMH  47 WVKQTPVHGLEWIG AI

TAYNQRFKG KAIL HCDR2 DPETGG  42 HCDR2 AIDPETGGTAYNQRFKG  48TTDKSSITAYMELRSLTSEDSAVYYCTR

W HCDR3 WNDGDY  43 HCDR3 WNDGDY  43 GQGTTLTVSS VLDVVMTQTPLSLSVTIGQPASISC

 50 LCDR1 KSSQSLLYSNGKTYLN  44 LCDR1 KSSQSLLYSNGKTYLN  44

WFQQRPGQSPKRLMY

GIPDRFSGS LCDR2 QVSKLDP  45 LCDR2 QVSKLDP  45 GSETDFTLKISRVEAEDLGLYYC

FGG LCDR3 LQGTYYPYT  46 LCDR3 LQGTYYPYT  46 GTKLEIK 3327 VHEVQLQQSGPELVKPGASVKMSCKASGYSFT

FMN  59 HCDR1 GYSFTGY  51 HCDR1 GYFMN  57 WVKQSHGKSLEWIG RI

TFYNQKFKG KATL HCDR2 NPYNGD  52 HCDR2 RINPYNGDTFYNQKFKG  58TVDKSSSTAHMELRSLTSEDSALYYCAS

HCDR3 EGDGYYWYFDV  53 HCDR3 EGDGYYWYFDV  53

WGAGTTVTVSS VL DIVLTQSPASLAVSLGQRATISC

 60 LCDR1 RASESVDNYGISFMN  54 LCDR1 RASESVDNYGISFMN  54

WFQQKPGQPPKLLIY

GVPARFSGSG LCDR2 AASNQGS  55 LCDR2 AASNQGS  55 SGTDFSLNIHPMEEDDTAMYFC

FGGG LCDR3 QQSKEVPRT  56 LCDR3 QQSKEVPRT  56 TKLEIK 3525 VHQVQLQQSGAELVRPGASVKLSCKASGYTFT

EMH  66 HCDR1 GYTFTDH  61 HCDR1 DHEMH  64 WVRQTPVHGLEWIG VI

TTYNQKFKG KATL HCDR2 DPDTGD  62 HCDR2 VIDPDTGDTTYNQKFKG  65TADKSSSTAYMDLRSLTSEDSAVFYCTR

W HCDR3 WTGGDY  63 HCDR3 WTGGDY  63 GHGTTLTVSS VLDVVMTQTPLSLSVTIGQPASISC

 50 LCDR1 KSSQSLLYSNGKTYLN  44 LCDR1 KSSQSLLYSNGKTYLN  44

WFQQRPGQSPKRLMY

GIPDRFSGS LCDR2 QVSKLDP  45 LCDR2 QVSKLDP  45 GSETDFTLKISRVEAEDLGLYYC

FGG LCDR3 LQGTYYPYT  46 LCDR3 LQGTYYPYT  46 GTKLEIK 3530 VHQVQLQQSGAELVRPGASVKLSCKASGYTFT

EMH  66 HCDR1 GYTFTDH  61 HCDR1 DHEMH  64 WVRQTPVHGLEWIG VI

TTYNQKFKG KATL HCDR2 DPDTGD  62 HCDR2 VIDPDTGDTTYNQKFKG  65TADKSSSTAYMDLRSLTSEDSAVFYCTR

W HCDR3 WTGGDY  63 HCDR3 WTGGDY  63 GHGTTLTVSS VLDAVMTQTPLSLSVTIGQPASISC

 70 LCDR1 KSSQSLLYSDGKTYLN  67 LCDR1 KSSQSLLYSDGKTYLN  67

WFQQRPGQSPKRLMY

GIPDRFSGS LCDR2 QVSKLDP  45 LCDR2 QVSKLDP  45 GSETDFTLKISRVEAEDLGVYYC

FGS LCDR3 LQGTYYPYT  46 LCDR3 LQGTYYPYT  46 GTKLEIK 4035 VHQVQLKESGPGLVAPSQSLSITCTVSGFSLT

DVH 101 HCDR1 GFSLT IY  93 HCDR1 IYDVH  99 WVRQSPGKGLEWLG VI

TDYNAAFIS RLSIS HCDR2 WSDGS  94 HCDR2 VIWSDGSTDYNAAFIS 100KDNSKSQVFFKMNSLQADDTAIYYCAR

HCDR3 NWVDQAWFAY  95 HCDR3 NWVDQAWFAY  95

WGQGTLVTVSA VL DIQMTQSPASLSASVGETITITC

W 102 LCDR1 RASKNIYSYLA  96 LCDR1 RASKNIYSYLA  96 YQQKQGKSPQLLVY

GVPSRFSGSGSGTQ LCDR2 NAKTLPE  97 LCDR2 NAKTLPE  97 FSLKINSLQPEDFGSYYC

FGAGTKLE LCDR3 QHHYGTPLT  98 LCDR3 QHHYGTPLT  98 LK 4035-062 VHQVQLQESGPGLVKPSETLSLTCTVSGFSLT

DVH 225 HCDR1 GFSLTIY  93 HCDR1 IYDVH  99 WVRQPPGKGLEWIG VI

TDYNPSLKS RVTIS HCDR2 WSDGS  94 HCDR2 VIWSDGSTDYNPSLKS 273KDTSKNQVSLKLSSVTAADTAVYYCAR

HCDR3 NWVDQAWFAY  95 HCDR3 NWVDQAWFAY  95

WGQGTLVTVSS VL DIQMTQSPSSLSASVGDRVTITC

W 229 LCDR1 RASKNIYSYLA  96 LCDR1 RASKNIYSYLA  96 YQQKPGKAPKLLVY

GVPSRFSGSGSGTD LCDR2 NAKTLPE  97 LCDR2 NAKTLPE  97 FTLTISSLQPEDFATYYC

FGQGTKLE LCDR3 QHHYGTPLT  98 LCDR3 QHHYGTPLT  98 IK 3934 VHQVQLQQSGPELVKPGASVKLSCKAAGYIFT

TIN 111 HCDR1 GYIFTDY 103 HCDR1 DYTIN 109 WVKQSPGQGLEWIG WI

RKYNDKFKG KATM HCDR2 YPGSGN 104 HCDR2 WIYPGSGNRKYNDKFKG 110TADKSSSTAYMQLSSLTSEDSAVYFCAR

HCDR3 ESNYVGYYAMDY 105 HCDR3 ESNYVGYYAMDY 105

WGQGTSVTVSS VL DVLMTQTPLSLPVSLGDQASISC

112 LCDR1 RSSQSVVNSNGNTYLE 106 LCDR1 RSSQSVVNSNGNTYLE 106

WYLQKPGQSPNLLIY

GVPDRFSGS LCDR2 KVSNRFS 107 LCDR2 KVSNRFS 107 GSGTDFTLKISRVEAEDLGVYYC

FGG LCDR3 FQGSHVPWT 108 LCDR3 FQGSHVPWT 108 GTKLEIK 3833 VHQVQLQQSGAELVRPGTSVKMSCKAAGYTFT

WIG 121 HCDR1 GYTFTNY 113 HCDR1 NYWIG 119 WVKQRPGHGLEWIG DI

TKYNEKFKG K HCDR2 YPGGIGGGY 114 HCDR2 DIYPGGIGGGYTKYNEKFKG 120ATLTADTSSSTAYMQLGSLTSEDSAIYFCSR

HCDR3 SETGRAMDY 115 HCDR3 SETGRAMDY 115

WGQGTSVTVSS VL DIQMTQSPSSLSASLGGKVTITC

W 122 LCDR1 KASQDINKYIA 116 LCDR1 KASQDINKYIA 116 YQHKPGKGPRLLIH

GIPSRFSGSGSGRD LCDR2 YTSTLKP 117 LCDR2 YTSTLKP 117 YSFSISDLEPEDIATYYC

FGGGTKLEI LCDR3 LQYDNLNT 118 LCDR3 LQYDNLNT 118 K 3631 VHEIQLQQSGPELVKPGASVKVSCKASGYSFT

NIY 131 HCDR1 GYSFTDY 123 HCDR1 DYNIY 129 WVKQSHGKSLEWIG YI

PGYNQKFRG KATL HCDR2 DPSNGG 124 HCDR2 YIDPSNGGPGYNQKFRG 130TVDKSSSTAFLHLNSLTSEDSAVYYCAR

HCDR3 RDNYGSGTMDY 125 HCDR3 RDNYGSGTMDY 125

WGQGTSVTVSS VL DIVMTQSQKFMSTSVGDRVSITC

W 132 LCDR1 KASQNVGTDVS 126 LCDR1 KASQNVGTDVS 126 YQQKPGKSPKPLIY

GVPDRFIGSGSGTD LCDR2 WASNRFT 127 LCDR2 WASNRFT 127 FTLTISNVQSEDLADYFC

FGAGTKLE LCDR3 EQYSIYPLT 128 LCDR3 EQYSIYPLT 128 LK 3732 VHEIQLQQSGPELVKPGASVKVSCKASGYSFT

NMY 140 HCDR1 GYSFTDD 133 HCDR1 DDNMY 138 WVKQSHGKSLEWIG YI

TGYNQKFKG KATL HCDR2 DPLNGG 134 HCDR2 YIDPLNGGTGYNQKFKG 139TVDKSSSTAFLHLMSLTSEDSAVYYCAR

HCDR3 RDNYATGTMDY 135 HCDR3 RDNYATGTMDY 135

WGQGTSVTVSS VL DIVMTQSQKFMSTSVGDRVSITC

W 141 LCDR1 KASKNVGTDVS 136 LCDR1 KASKNVGTDVS 136 YQQKPGKSPKPLIY

GVPDRFTGSGSGTD LCDR2 WASNRFT 127 LCDR2 WASNRFT 127 FTLTINNVQSEDLADYFC

FGAGTKLE LCDR3 EQYSSYPLT 137 LCDR3 EQYSSYPLT 137 LK 4338 VHEVQLQQSGPELVKPGASVKISCKASGYTFT

NMD 151 HCDR1 GYTFTDY 11 HCDR1 DYNMD 149 WVKQSHGKSLEWIG NI

TGYNQRFKN KATL HCDR2 YPINGY 142 HCDR2 NIYPINGYTGYNQRFKN 150TVDKSSSTAYMELHSLTSEDSAVYYCAR

HCDR3 DSNYVGWYFDV 143 HCDR3 DSNYVGWYFDV 143

WGAGTTVTVSS VL DVVMTQTPLSLPVSLGDQASISC

152 LCDR1 RSSQSLVHSNGNTYLH 144 LCDR1 RSSQSLVHSNGNTYLH 144

WYLQKPGQSPKLLIY

GVPDRFSGS LCDR2 KVSNRFS 107 LCDR2 KVSNRFS 107 GSGTDFTFKISRVEAEDLGVYFC

FGG LCDR3 SQSTHVPRT 145 LCDR3 SQSTHVPRT 145 GTKLEIK VLDIVLTQSPASLTVSLGQRATFSC

153 LCDR1 RASKSVSTSGYSYMH 146 LCDR1 RASKSVSTSGYSYMH 146

WYQQKPGQPPKLLIY

GVPARFTGSG LCDR2 FTSDLEP 147 LCDR2 FTSDLEP 147 SGTDFTLNIHPVEEEDAATYYC

FGGG LCDR3 QHSRELPYP 148 LCDR3 QHSRELPYP 148 TKLEIK 4540 VHQVQLQQSGPELVKPGASVKISCKASGYTFA

YIN 161 HCDR1 GYTFADY 154 HCDR1 DYYIN 159 WVKQRPGQGLEWIG WI

TYYNEKFKG KATL HCDR2 FPGSGS 155 HCDR2 WIFPGSGSTYYNEKFKG 160TVDKSSSTAYMLLSSLTSEDSAVYFCAR

HCDR3 GDSGRAMDY 156 HCDR3 GDSGRAMDY 156

WGQGTSVTVSS VL DIQMTQSPSSLSASLGGKVTITC

W 162 LCDR1 KASQDINKYIA 116 LCDR1 KASQDINKYIA 116 YQHKPGKGPRLLIH

GIPSRFSGSGSGRD LCDR2 YTSTLQS 157 LCDR2 YTSTLQS 157 YSFSISNLEPEDNATYYC

FGAGTKLEL LCDR3 LQYDNLLT 158 LCDR3 LQYDNLLT 158 K 4540-063 VHQVQLVQSGAELKKPGASVKVSCKASGYTFA

YMN 258 HCDR1 GYTFADY 154 HCDR1 DYYMN 276 WVRQAPGQGLEWMG WI

TYYNQKFQG RVTM HCDR2 FPGSGS 155 HCDR2 WIFPGSGSTYYNQKFQG 277TVDKSSSTAYMELSRLRSDDTAVYYCAR

HCDR3 GDSGRAMDY 156 HCDR3 GDSGRAMDY 156

WGQGTLVTVSS VL DIQMTQSPSSLSASVGDRVTITC

W 261 LCDR1 QASQDINKYLA 274 LCDR1 QASQDINKYLA 274 YQHKPGKAPKLLIH

GVPSRFSGSGSGTD LCDR2 YTSTLET 275 LCDR2 YTSTLET 275 FTFTISSLQPEDIATYYC

FGGGTKVEI LCDR3 LQYDNLLT 158 LCDR3 LQYDNLLT 158 K 4540-033 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFA

YIN 256 HCDR1 GYTFADY 154 HCDR1 DYYIN 159 WVRQAPGQGLEWMG WI

TYYAQKLQG RVTM HCDR2 FPGSGS 155 HCDR2 WIFPGSGSTYYAQKLQG 278TTDTSTSTAYMELRSLRSDDTAVYYCAR

HCDR3 GDSGRAMDY 156 HCDR3 GDSGRAMDY 156

WGQGTLVTVSS VL DIQMTQSPSSLSASVGDRVTITC

W 261 LCDR1 QASQDINKYLA 274 LCDR1 QASQDINKYLA 274 YQHKPGKAPKLLIH

GVPSRFSGSGSGTD LCDR2 YTSTLET 275 LCDR2 YTSTLET 275 FTFTISSLQPEDIATYYC

FGGGTKVEI LCDR3 LQYDNLLT 158 LCDR3 LQYDNLLT 158 K 4237 VHQAHLKESGPGLVAPSQSLSITCTVSGFSLT

DVH 171 HCDR1 GFSLTDY 163 HCDR1 DYDVH 169 WVRQSPGKGLEWLG VI

TDYNTAFIS RLTIS HCDR2 WNDGS 164 HCDR2 VIWNDGSTDYNTAFIS 170KDNSKSQVFFKMNSLQADDTAIYYCAR

HCDR3 NWYGGYWFAY 165 HCDR3 NWYGGYWFAY 165

WGQGTLVTVSA VL DIQMTQSPASLSASAGETVTITC

W 172 LCDR1 RSSENIYSYLA 166 LCDR1 RSSENIYSYLA 166 YQQKQGKSPQLLVY

GVPSRFSGSGSVTQ LCDR2 NANALAE 167 LCDR2 NANALAE 167 FSLKINSLQPEDFGSYYC

FGSGTKLE LCDR3 QHHYGTPFT 168 LCDR3 QHHYGTPFT 168 IK 4439 VHEIQLQQSGAELVKPGASVKISCKASDYSFT

NMN 271 HCDR1 DYSFTGY 266 HCDR1 GYNMN 269 WVMQSHGKSLEWIG NI

T SFNQKFMG KATL HCDR2 HPYYGG 267 HCDR2 NIHPYYGGTSFNQKFMG 270TADKSSSTAYMQLNSLTSEDSAVYYCAR

HCDR3 ERSNFHALDY 268 HCDR3 ERSNFHALDY 268

WGQGTSVTVSS VL DIVLTQSPASLTVSLGQRATFSC

272 LCDR1 RASKSVSTSGYSYMH 146 LCDR1 RASKSVSTSGYSYMH 146

WYQQKPGQPPKLLIY

GVPARFTGSG LCDR2 FTSDLEP 147 LCDR2 FTSDLEP 147 SGTDFTLNIHPVEEEDAATYYC

FGGG LCDR3 QHSRELPYP 148 LCDR3 QHSRELPYP 148 TKLEIK

TABLE 2Nucleotide sequences of heavy chain variable regions (VHs) and light chain variable regions(VLs) of exemplary antibody molecules SEQ ID Antibody ChainNucleotide Sequence NO 2218 VHGATGTACAGCTTCAGGAGTCAGGACCTGGCCTCGTGAAACCTTCTCAGTCTCTGTCTCTCACCTGCTCTGTCACTGGC 71TACTCCATCACCAGTGGTTATTACTGGAACTGGATCCGGCAGTTTCCAGGAAACAAACTGGAATGGATGGGCTACATAAGCTACGATGGTTACAATAACTACAACCCATCTCTCAAAAATCGAATCTCCATCACTCGTGACACATCTAAGAACCAGTTTTTCCTGAAGTTGAATTCTGTGACTACTGAGGACACAGCCACATATTACTGTGCAAACTACTATGATTACGAAGACTGGTACTTCGGTGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA VLGACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTATGTCTCTAGGGAAGAGGGCCACCATCTCCTGCAGAGCCAGC 72GAAAGTGTCAGTATTATTGGTACTAATTCAATACACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCATGCATCCAACCTAGAAACTGGAGTCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGAACAGACTTCACCCTCACCATTGATCCTGTGGAGGAAGATGATGTTGCAATCTATTACTGTCTGCAAAGTAGGAAGATTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 2419 VHCAGGTCCAGCTGCAGCAGTCTGGAGCTGAGCTGGTGAAACCCGGGGCATCAGTGAGGCTGTCCTGCGAGGCTTCTGGC 73TACACCTTCACGGACTATACTATACACTGGGTAAAGCAGAGGTCTGGACAGGGTCTTGAGTGGATTGGATGGATTTACCCTCTAAGAGGTAGTATAAACTACAATGAGAAATTCAAGGACAAGGCCACATTGACTGCGGACAAATCCTCCAGCACAGTCTATTTGGAGCTTGGTAGATTGACATCTAAGGACTCTGCGGTCTATTTCTGTGCAAGACACGGAGCCTACTATAGTAACGCCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA VLAACATTGTAATGACCCAATCTCCAGCTTCATTGGCTGTGTCTCTAGGTCAGAGGGCCACCATCTCCTGCAGAGCCAGC 74GAGAGTGTTGATAATGATGGCATTAGATTTATGCACTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCGTGCATCCAACCTAGAATCTGGGATCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCACTATTAATCCTGTGGAGACTGATGATGTTGCAACCTATTACTGTCAGCAAAGTAATAAGGATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGCTGAAA 2419-1305 VHCAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGC304TACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-1306 VHCAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGC304TACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC VLGAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCC306GAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 2419-1310 VHCAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGC304TACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCAACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC VLGACATTGTAATGACCCAGTCTCCCGATAGCCTCGCTGTCTCACTCGGAGAACGCGCAACCATCAACTGCAAGTCCTCC318CAAAGCGTTGACAATGACGGCATTAGGTTTTTGCACTGGTACCAGCAGAAACCCGGTCAACCTCCTAAGTTGCTCATTTACCGAGCATCTACCCGCGAGTCAGGAGTACCTGATCGCTTTTCCGGTAGCGGTAGTGGAACAGATTTTACTCTGACCATTAGTTCACTCCAGGCAGAAGATGTGGCTGTCTACTACTGCCAACAGTCAAATAAAGACCCTTATACCTTCGGTGGGGGTACCAAAGTAGAGATCAAA 2419-0806 VHGAGGTCCAGTTGGTCCAGTCAGGAGCCGAAGTCAAGAAGCCTGGGGAAAGCCTGAAAATAAGTTGCAAAGCTAGTGGA307TATACATTTACAGATTATACCATTCATTGGGTCCGGCAAATGCCAGGAAAAGGCTTGGAGTGGATGGGGTGGATTTATCCCCTCCGAGGCTCAATAAATTATAGTCCTAGTTTTCAGGGGCAGGTAACTATTAGCGCTGATAAAAGTATTTCTACAGTTTATTTGCAGTGGAGTTCATTGAAGGCTAGTGACACCGCTATGTATTTCTGCGCTAGACATGGTGCATATTATTCAAATGCCTTCGACTATTGGGGCCAGGGCACCCTCGTCACTGTGAGTTCC VLGAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCC306GAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 2419-0205 VHCAGGTGCAACTTGTTCAGTCAGGGGCTGAAGTAAAGAAGCCAGGCTCATCAGTCAAGGTATCATGCAAAGCATCTGGC308TATACATTTACAGATTACACCATTCACTGGGTGAGGCAAGCTCCCGGTCAAGGTCTCGAGTGGATGGGGTGGATATACCCTCTCAGAGGCTCTATAAATTACGCTCAGAAATTTCAAGGGAGAGTTACAATTACTGCTGATAAAAGTACCAGCACTGCTTATATGGAGCTTTCCTCACTTCGTTCAGAGGACACCGCCGTTTACTTTTGTGCCCGGCATGGTGCCTATTATTCAAATGCCTTCGATTATTGGGGGCAGGGAACTTTGGTCACAGTTTCATCT VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-0406 VHCAAGTTCAACTTGTCCAAAGTGGGGCTGAAGTTAAAAAACCTGGATCATCAGTCAAGGTTTCATGCAAAGCCAGCGGT309TACACATTTACAGACTATACAATACATTGGGTTCGACAGGCTCCCGGGCAAGGGCTCGAATGGATGGGATGGATTTATCCCCTCAGGGGCTCAATTAACTATGCTGAGAAATTTAAGGGTCGTGTAACACTCACCGCCGATAAATCCACCTCAACCGTATATATGGAGCTTTCTTCTCTTCGCTCTGAAGATACCGCCGTCTATTTCTGCGCACGACACGGGGCATACTATTCTAATGCTTTTGACTACTGGGGACAAGGGACACTTGTGACCGTTAGTAGC VLGAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCC306GAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 2419-0605 VHCAGGTGCAGTTGGTCCAGAGCGGGGCAGAGGTTAAGAAGCCTGGGGCCTCAGTAAAGGTATCCTGCAAGGCTTCTGGG319TACACCTTCACAGATTACACTATTCATTGGGTGCGCCAAGCACCTGGTCAAGGCCTTGAATGGATGGGATGGATTTACCCCTTGCGAGGGAGTATTAATTATGCACAGAAGTTCCAGGGAAGGGTTACTCTTACCGCCGACAAGTCCACATCAACCGTTTACATGGAGCTTTCCTCTCTCAGGTCCGAAGACACTGCTGTATATTTCTGCGCTCGGCATGGGGCTTATTACAGCAACGCCTTCGATTACTGGGGTCAGGGTACATTGGTCACAGTGTCCAGT VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-0805 VHGAGGTCCAGTTGGTCCAGTCAGGAGCCGAAGTCAAGAAGCCTGGGGAAAGCCTGAAAATAAGTTGCAAAGCTAGTGGA307TATACATTTACAGATTATACCATTCATTGGGTCCGGCAAATGCCAGGAAAAGGCTTGGAGTGGATGGGGTGGATTTATCCCCTCCGAGGCTCAATAAATTATAGTCCTAGTTTTCAGGGGCAGGTAACTATTAGCGCTGATAAAAGTATTTCTACAGTTTATTTGCAGTGGAGTTCATTGAAGGCTAGTGACACCGCTATGTATTTCTGCGCTAGACATGGTGCATATTATTCAAATGCCTTCGACTATTGGGGCCAGGGCACCCTCGTCACTGTGAGTTCC VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-0105 VHCAAGTGCAGTTGGTCCAGAGTGGAGCAGAGGTGAAGAAGCCTGGTGCTTCCGTCAAGGTGAGTTGCAAGGCATCTGGT310TATACTTTCACTGACTACACAATTCATTGGGTCAGGCAGGCCCCTGGACAGGGACTGGAATGGATGGGATGGATCTATCCACTTAGAGGATCAATCAACTATGCTCAAAAGTTCCAGGGTCGTGTAACAATGACCGCAGACAAAAGTATCTCAACTGTATACATGGAATTGTCCCGATTGAGGAGCGACGACACAGCCGTATATTATTGTGCCAGGCACGGAGCCTACTACAGTAATGCCTTCGACTACTGGGGGCAGGGCACCCTTGTTACCGTGTCCAGC VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-1204 VHCAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGA311TATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC VLGAAATTGTAATGACCCAGAGCCCCGCCACCCTTAGTGTGTCCCCAGGCGAGAGGGCCACTCTTTCTTGCCGCGCAAGC312GAATCCGTAGACAACGATGGTATAAGATTTTTGCATTGGTATCAGCAAAAGCCAGGCCAGGCACCCCGGCTTCTCATCTACAGAGCTAGCACCCTCGAAACTGGAATCCCCGCTCGTTTTTCAGGATCTGGTAGCGGAACAGAATTTACTTTGACAATTAGTAGTTTGCAGTCAGAGGACTTTGCTGTCTATTATTGCCAGCAGTCTAATAAAGATCCATACACCTTCGGCGGAGGGACCAAAGTAGAGATTAAA 2419-1210 VHCAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGA311TATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC VLGACATTGTAATGACCCAGTCTCCCGATAGCCTCGCTGTCTCACTCGGAGAACGCGCAACCATCAACTGCAAGTCCTCC318CAAAGCGTTGACAATGACGGCATTAGGTTTTTGCACTGGTACCAGCAGAAACCCGGTCAACCTCCTAAGTTGCTCATTTACCGAGCATCTACCCGCGAGTCAGGAGTACCTGATCGCTTTTCCGGTAGCGGTAGTGGAACAGATTTTACTCTGACCATTAGTTCACTCCAGGCAGAAGATGTGGCTGTCTACTACTGCCAACAGTCAAATAAAGACCCTTATACCTTCGGTGGGGGTACCAAAGTAGAGATCAAA 2419-1406 VHCAAGTTCAGTTGGTGCAAAGCGGGGCAGAAGTGAAGAAACCTGGTGCTTCTGTGAAAGTTTCCTGCAAGGCCAGCGGC313TACACCTTTACTGATTACACAATACACTGGGTACGGCAGGCAACTGGGCAAGGATTGGAATGGATGGGGTGGATATACCCATTGCGAGGGTCTATAAACTACGCACAGAAATTTCAAGGTCGAGTAACAATGACAGCCGACAAATCAATAAGCACCGTTTATATGGAACTCTCATCTCTCAGGAGTGAGGATACCGCCGTGTATTTCTGCGCACGACACGGTGCATATTACTCAAACGCTTTCGACTATTGGGGCCAGGGCACCCTTGTGACTGTTAGTAGC VLGAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCC306GAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 2419-1205 VHCAAGTGCAGCTCGTTCAGTCTGGCGCAGAAGTGAAGAAGCCAGGAGCTTCCGTTAAAGTGTCCTGTAAAGCCTCTGGA311TATACATTCACAGATTATACAATTCACTGGGTGAGACAAGCAACCGGTCAAGGTCTCGAATGGATGGGCTGGATATACCCCCTCCGAGGTTCCATCAACTACGCTCAAAAATTCCAAGGACGAGTCACTATGACAGCAAACAAGAGTTCCTCCACTGTATATATGGAACTCTCTAGTTTGCGCTCTGAAGACACCGCCGTGTACTTCTGTGCCAGGCACGGCGCATACTATTCTAATGCATTTGACTATTGGGGGCAGGGCACATTGGTAACAGTTAGTTCC VLGAGATAGTAATGACTCAGTCTCCCGCTACACTTAGTGTAAGCCCAGGGGAGCGAGCAACCCTCAGTTGCAGAGCATCT305GAGAGTGTTGATAATGATGGAATACGTTTTCTCCATTGGTATCAACAAAAACCAGGGCAGGCCCCCAGATTGCTGATCTACCGTGCTTCCAATCGCGAGACTGGCATTCCTGCACGTTTCAGCGGCAGCGGCTCCGGAACCGAGTTTACACTTACTATTAGCTCACTCCAGTCTGAAGACTTCGCTGTGTATTACTGTCAGCAATCCAACAAGGACCCATACACTTTCGGAGGCGGCACTAAGGTTGAGATCAAA 2419-0206 VHCAGGTGCAACTTGTTCAGTCAGGGGCTGAAGTAAAGAAGCCAGGCTCATCAGTCAAGGTATCATGCAAAGCATCTGGC308TATACATTTACAGATTACACCATTCACTGGGTGAGGCAAGCTCCCGGTCAAGGTCTCGAGTGGATGGGGTGGATATACCCTCTCAGAGGCTCTATAAATTACGCTCAGAAATTTCAAGGGAGAGTTACAATTACTGCTGATAAAAGTACCAGCACTGCTTATATGGAGCTTTCCTCACTTCGTTCAGAGGACACCGCCGTTTACTTTTGTGCCCGGCATGGTGCCTATTATTCAAATGCCTTCGATTATTGGGGGCAGGGAACTTTGGTCACAGTTTCATCT VLGAGATAGTTATGACTCAGTCTCCCGCCACACTTTCAGTAAGTCCCGGTGAACGCGCCACCCTGTCCTGCCGTGCTTCC306GAATCAGTGGATAATGACGGCATTAGGTTTTTGCACTGGTACCAACAAAAGCCCGGACAGGCCCCCCGCCTGCTGATATATCGTGCATCAACACGAGCAACAGGGATCCCCGCTCGATTTAGTGGATCCGGAAGCAGGACCGAATTTACACTTACCATTTCCTCACTTCAGTCAGAAGATTTCGCCGTTTACTACTGTCAGCAGTCAAATAAGGATCCTTACACATTTGGGGGCGGTACAAAAGTCGAGATCAAA 2621 VHGAGGTCCAGCTTCAGCAGTCTGGAGCTGAGCTGGTGAGGCCTGGGTCCTCAGTGAAGATGTCCTGCAAGACTTCTGGA 75TATACTTTCACAAGCTACGGTATAAACTGGGTGAAGCAGAGGCCTGGACAGGGCCTGGAATGGATTGGATATATTTATATTGGAAATGGTTATGCTGAGTACAATGAGAGGTTCAAGGGCAAGGCCACACTGACTTCAGACACATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCAATCTATTTCTGTGCACTATACTATCCCTGGTTTACTTACTGGGGCCAGGGGACTCTGGTCACTGTCTCTGCA VLGACATCCAGATGACTCAGTCTCCAGCCTCCCTTTCTGCATCTGTGGGAGATTCTGTCACCATCACATGTCGAGCAAGT 76GAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCTGAAGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAATTATTACTGTCAACATCATTATGATACTCCGTTCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 2922 VHCAGGTTCAGCTGCACCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGACTTCTGGC 77TACACCTTCACAAGCTACGATGTCTTCTGGGTGAAGCAGAGGCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTAGAGATAGTAGTACTAAATACAATGAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACACATCCTCCAGCACAGCATACATGGAGCTCCACAGCCTGACATCTGAGGACTCTGCGGTCTATTTCTGTGCAAAAGAGGGGTATGATTATGACAAGAGGGGCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA VLGACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCATCATCTCCTGCAAGGCCAGC 78CAAAGTGTCAGTTTTGCTGGTACTAATTTAATGCACTGGTACCAACAGAGACCAGGGCAGCAACCCAAACTCCTCATCTATCGTGCATCCAACCTAGAACCTGGGGTTCCTACCAGGTTTAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCAATATCCATCCTGTGGAGGAAGATGATGCTGCAACCTATTACTGTCAGCAAAGTAGGGAATATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 3125 VHCAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGC 79TACACTTTTACTGACTATGAAATGCACTGGGTGAAGCAGACACCTGTGCATGGCCTGGAATGGATTGGAGCTATTGATCCTGAAACTGGTGGTACTGCCTACAATCAGAGGTTCAAGGGCAAGGCCATACTGACTACAGACAAATCCTCCATCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTATTACTGTACAAGATGGAATGATGGCGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA VLGATGTTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCCATTTCTTGCAAGTCAAGT 80CAGAGCCTCTTATACAGTAATGGAAAGACATATTTGAATTGGTTTCAACAGAGGCCTGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAAACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGACTTTATTACTGCTTGCAAGGTACATATTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 3327 VHGAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGT 81TACTCCTTTACTGGCTACTTTATGAACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGACGTATTAATCCTTACAATGGTGATACTTTCTACAACCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAATCCTCTAGCACAGCCCACATGGAGCTCCGGAGCCTGACATCTGAGGACTCTGCACTCTATTATTGTGCAAGCGAAGGTGATGGTTACTACTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA VLGACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAGAGCCAGC 82GAAAGTGTTGATAATTATGGCATTAGTTTTATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATGCTGCATCCAACCAAGGATCCGGGGTCCCTGCCAGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCAGCCTCAACATCCATCCTATGGAGGAGGATGATACTGCAATGTATTTCTGTCAGCAAAGTAAGGAGGTTCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 3525 VHCAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCGGGC 83TACACATTTACTGACCATGAAATGCACTGGGTGAGACAGACACCTGTGCATGGCCTGGAATGGATTGGAGTTATTGATCCTGACACTGGTGATACTACCTACAATCAGAAATTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGGACCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTTTTACTGTACACGGTGGACTGGGGGGGACTACTGGGGCCATGGCACCACTCTCACAGTCTCCTCA VLGATGTTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCCATTTCTTGCAAGTCAAGT 80CAGAGCCTCTTATACAGTAATGGAAAGACATATTTGAATTGGTTTCAACAGAGGCCTGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAAACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGACTTTATTACTGCTTGCAAGGTACATATTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 3530 VHCAGGTTCAACTGCAGCAGTCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCGGGC 83TACACATTTACTGACCATGAAATGCACTGGGTGAGACAGACACCTGTGCATGGCCTGGAATGGATTGGAGTTATTGATCCTGACACTGGTGATACTACCTACAATCAGAAATTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGGACCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTTTTACTGTACACGGTGGACTGGGGGGGACTACTGGGGCCATGGCACCACTCTCACAGTCTCCTCA VLGATGCTGTGATGACCCAGACTCCACTGTCTTTGTCGGTTACCATTGGACAACCAGCCTCTATCTCTTGCAAGTCGAGT 84CAGAGCCTCTTATATAGTGATGGAAAGACATATTTGAATTGGTTCCAACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATGTATCAGGTGTCCAAACTGGACCCTGGCATCCCTGACAGGTTCAGTGGCAGTGGATCAGAGACAGATTTTACACTTAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTACTGCTTGCAAGGTACATATTATCCGTATACGTTCGGATCGGGGACCAAGCTGGAAATAAAA 4035 VHCAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGT173TTCTCATTAACCATCTATGATGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGATGGAAGCACAGACTATAATGCAGCTTTCATATCTAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTGATGACACAGCCATATACTACTGTGCCAGAAATTGGGTCGACCAGGCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA VLGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTATCACCATCACATGTCGAGCAAGT174AAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTACCAGAAGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATCATTATGGTACTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 4035-062 VHCAGGTACAACTCCAGGAATCCGGGCCTGGGCTCGTCAAACCAAGCGAAACACTCTCTCTCACCTGCACCGTTTCTGGG299TTTTCTCTTACTATCTATGACGTACATTGGGTAAGGCAACCACCCGGGAAGGGGCTGGAGTGGATCGGTGTAATCTGGTCAGATGGATCTACAGACTACAACCCATCCCTTAAAAGCAGGGTGACCATTTCTAAGGACACTTCCAAGAACCAAGTATCCCTTAAATTGTCCTCTGTAACCGCAGCAGACACCGCAGTTTACTACTGCGCACGAAATTGGGTTGACCAAGCATGGTTTGCATATTGGGGACAGGGAACTCTTGTCACTGTGTCTTCA VLGATATTCAAATGACCCAATCCCCCTCATCACTTTCAGCATCTGTCGGTGATCGGGTCACCATTACTTGCAGAGCCAGT300AAGAATATCTACAGCTACCTGGCTTGGTATCAGCAAAAACCTGGTAAGGCCCCTAAACTTCTCGTTTACAATGCTAAGACCCTTCCCGAGGGAGTTCCTTCCAGGTTTTCCGGTAGCGGGAGTGGAACAGATTTCACCTTGACTATTTCTAGCTTGCAGCCCGAGGATTTCGCTACATACTACTGCCAGCATCACTATGGAACCCCCCTGACCTTCGGTCAGGGAACCAAGCTCGAGATCAAA 3934 VHCAGGTCCAACTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCTGCTGGC175TACATCTTCACTGACTATACTATAAACTGGGTGAAGCAGAGTCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTGGAAGTGGTAATCGTAAATACAATGACAAGTTCAAGGGCAAGGCCACAATGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACCTCTGAGGATTCTGCGGTCTATTTCTGTGCAAGAGAGAGTAACTACGTGGGGTACTATGCTATGGACTATTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA VLGATGTTTTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGT176CAGAGCGTTGTAAATAGTAATGGAAACACCTATTTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAATCTCCTGATCTACAAAGTTTCCAATCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCGGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGTTTTCAAGGTTCACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA 3833 VHCAGGTCCAGCTGCAGCAGTCTGGAGCTGAGCTGGTAAGGCCTGGGACTTCAGTGAAGATGTCCTGCAAGGCTGCTGGA177TACACCTTCACAAACTACTGGATAGGTTGGGTAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATTGGAGATATTTACCCTGGAGGTATAGGAGGTGGTTATACTAAGTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACACATCCTCCAGCACAGCCTACATGCAGCTCGGCAGCCTGACATCTGAGGACTCTGCCATCTATTTCTGTTCAAGATCGGAAACTGGACGGGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA VLGACATCCAGATGACACAGTCTCCATCCTCACTGTCTGCATCTCTGGGAGGCAAAGTCACCATCACTTGCAAGGCAAGC178CAAGACATTAATAAGTATATAGCTTGGTACCAACACAAGCCTGGAAAAGGTCCTAGGCTGCTCATACATTACACATCTACATTAAAGCCAGGCATCCCATCAAGGTTCAGTGGAAGTGGGTCTGGGAGAGATTATTCCTTCAGCATCAGTGACCTGGAGCCTGAAGATATTGCAACTTATTATTGTCTACAGTATGATAATCTGAACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA 3631 VHGAGATCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGGTGTCCTGCAAGGCTTCTGGT179TATTCATTCACTGACTACAACATCTACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTGATCCTTCCAATGGTGGTCCTGGCTACAACCAGAAGTTCAGGGGCAAGGCCACATTGACTGTTGACAAGTCCTCCAGCACAGCCTTCCTGCATCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAAGGGACAACTACGGCTCGGGGACTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA VLGACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGTAAGGCCAGT180CAGAATGTGGGTACTGATGTATCCTGGTATCAACAGAAACCAGGGAAATCTCCTAAACCACTGATTTACTGGGCATCAAACCGGTTCACTGGAGTCCCTGATCGCTTCATAGGTAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAATGTGCAGTCTGAAGACTTGGCAGATTATTTCTGTGAGCAATATAGCATCTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 3732 VHGAGATCCAGCTGCAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCGTCAGTGAAGGTATCCTGCAAGGCTTCTGGT181TACTCATTCACTGACGACAACATGTACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTGATCCTCTCAATGGTGGTACTGGCTACAACCAGAAATTCAAGGGCAAGGCCACACTGACTGTTGACAAGTCCTCCAGCACAGCCTTCCTGCATCTCAACAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGAAGGGACAACTACGCCACGGGGACTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA VLGACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGCAAGGCCAGT182AAGAATGTGGGTACTGATGTATCCTGGTATCAACAGAAACCAGGGAAATCTCCTAAACCACTGATTTACTGGGCATCAAACCGGTTCACTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAATGTGCAGTCTGAAGACTTGGCAGATTATTTCTGTGAGCAATATAGCAGCTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA 4338 VHGAGGTCCAGCTGCAGCAGTCTGGCCCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGGA183TACACATTCACTGACTACAACATGGACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTTATCCTATCAATGGTTATACTGGCTACAACCAGAGGTTCAAGAACAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAACTCCACAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGCGCAAGAGATAGTAACTACGTTGGCTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA VLGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGT184CAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACATTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA VLGACATTGTGCTGACACAGTCTCCTGCTTCCTTAACTGTATCTCTGGGGCAGAGGGCCACCTTCTCATGCAGGGCCAGC185AAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATTTTACATCCGACCTAGAACCTGGGGTCCCTGCCAGGTTCACTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACCCCTTCGGAGGGGGGACCAAGTTGGAAATAAAA 4540 VHcaggtccagctacagcagtctggacctgagctggtgaagcctggggcttcagtgaagatatcctgcaaggcttctggc186tacaccttcgctgactactatataaactgggtgaagcagaggcctggacagggacttgagtggattggatggatttttcctggaagtggtagtacttactacaatgagaagttcaagggcaaggccacacttactgtagacaaatcctccagcacagcctacatgttgctcagcagcctgacctctgaggactctgcggtctatttctgtgcaagaggggactccggtagggctatggactactggggtcaaggaacctcagtcaccgtctcctca VLgacatccagatgacacagtctccatcctcactgtctgcatctctgggaggcaaagtcaccatcacttgcaaggcaagc187caagacattaacaaatatatagcttggtaccaacacaagcctggaaaaggtcctaggctgctcatacattacacatctacattacagtcaggcatcccatcaaggttcagtggaagtgggtctgggagagattattccttcagcatcagcaacctggagcctgaagataatgcaacttattattgtctacagtatgataatcttctcacgttcggtgctgggaccaagctggagctgaaa 4540-063 VHCAAGTCCAGCTCGTACAGAGCGGGGCAGAGCTGAAGAAGCCTGGGGCCTCCGTCAAGGTCTCCTGTAAGGCTTCTGGT301TACACATTTGCCGACTACTACATGAACTGGGTACGGCAAGCCCCAGGTCAAGGGCTGGAATGGATGGGATGGATTTTTCCAGGGAGCGGCAGCACTTACTACAACCAGAAATTTCAAGGTCGTGTGACAATGACCGTGGATAAAAGCAGCTCTACAGCTTACATGGAGCTTTCCCGCTTGAGGTCCGATGATACTGCCGTATATTATTGTGCCCGTGGTGACTCAGGTAGGGCCATGGACTATTGGGGACAGGGCACCCTCGTGACCGTGTCCAGC VLGATATCCAGATGACACAATCCCCTTCATCCTTGAGCGCATCAGTTGGCGACAGGGTCACCATAACTTGTCAGGCTAGT302CAGGATATTAACAAGTACCTGGCTTGGTATCAACACAAGCCTGGAAAGGCCCCCAAATTGCTGATTCACTACACCTCTACATTGGAAACTGGCGTACCCAGTCGCTTTTCTGGGAGTGGAAGCGGAACTGATTTCACTTTCACTATATCCAGTCTTCAGCCAGAAGATATCGCAACTTACTATTGTCTTCAGTATGATAACTTGCTTACTTTCGGAGGAGGGACCAAAGTTGAAATCAAG 4540-033 VHCAGGTGCAGTTGGTCCAATCCGGGGCTGAGGTGAAGAAGCCTGGGGCCTCTGTTAAAGTTAGTTGCAAGGCATCAGGC303TACACCTTCGCTGACTACTACATCAACTGGGTTAGACAGGCCCCCGGGCAGGGGTTGGAGTGGATGGGTTGGATTTTTCCAGGATCAGGTTCAACATATTACGCACAAAAACTGCAAGGTAGAGTAACCATGACAACTGATACTAGCACCTCCACAGCCTATATGGAACTCCGCTCTCTCAGGAGTGACGATACAGCCGTTTATTACTGCGCCCGTGGGGATTCAGGCCGTGCAATGGATTACTGGGGTCAAGGGACCCTCGTGACCGTAAGTTCA VLGATATCCAGATGACACAATCCCCTTCATCCTTGAGCGCATCAGTTGGCGACAGGGTCACCATAACTTGTCAGGCTAGT302CAGGATATTAACAAGTACCTGGCTTGGTATCAACACAAGCCTGGAAAGGCCCCCAAATTGCTGATTCACTACACCTCTACATTGGAAACTGGCGTACCCAGTCGCTTTTCTGGGAGTGGAAGCGGAACTGATTTCACTTTCACTATATCCAGTCTTCAGCCAGAAGATATCGCAACTTACTATTGTCTTCAGTATGATAACTTGCTTACTTTCGGAGGAGGGACCAAAGTTGAAATCAAG 4237 VHCAGGCGCACCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGT188TTCTCATTAACCGACTATGATGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAATGATGGAAGCACAGACTATAATACAGCTTTCATATCTAGACTGACCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTGATGACACAGCCATATACTACTGTGCCAGAAATTGGTATGGTGGCTACTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA VLGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGCGGGAGAAACTGTCACCATCACATGTCGATCAAGT189GAGAATATTTACAGTTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTAGTCTATAATGCAAATGCCTTAGCAGAAGGTGTGCCATCGAGGTTCAGTGGCAGTGGATCAGTCACACAGTTTTCTCTGAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATCATTATGGTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA 4439 VHGAGATCCAGCTGCAGCAGTCTGGAGCTGAACTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGGCTTCTGAT297TACTCATTCACTGGCTACAACATGAACTGGGTGATGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTCATCCTTACTATGGTGGTACTAGCTTCAATCAGAAGTTCATGGGCAAGGCCACATTGACTGCAGACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGCCTGACATCTGAAGACTCTGCAGTCTATTACTGTGCAAGAGAGAGAAGTAACTTCCATGCTCTGGACTACTGGGGTCAGGGAACCTCAGTCACCGTCTCCTCA VLGACATTGTGCTGACACAGTCTCCTGCTTCCTTAACTGTATCTCTGGGGCAGAGGGCCACCTTCTCATGCAGGGCCAGC298AAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATTTTACATCCGACCTAGAACCTGGGGTCCCTGCCAGGTTCACTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACCCCTTCGGAGGGGGGACCAAGTTGGAAATAAAA

TABLE 5The Amino Acid Sequences of the Heavy Chain Variable Region (VH) and Light Chain VariableRegion (VL) of the Exemplary Humanized Anti-APRIL Antibodies Are Provided As Follows.SEQ Antibody ID Chain Amino Acid Sequence NO >Hu_2218_VH01QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYWNWIRQHPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQF190 SLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS >Hu_2218_VH02QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYWSWIRQHPGKGLEWIGYISYDGYTYYNPSLKSRVTISVDTSKNQF191 SLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS >Hu_2218_VH03QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYYWNWIRQHPGKGLEWIGYISYDGYNNYNPSLKSRVTISRDTSKNQF192 SLKLSSVTAADTAVYYCARYYDYEDWYFGVWGQGTMVTVSS >Hu_2218_VH04QVQLQQWGAGLLKPSETLSLTCAVYGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQF193 SLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS >Hu_2218_VH05QVQLQQWGAGLVKPSETLSLTCAVYGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISRDTSKNQF194 SLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS >Hu_2218_VH06QVQLQESGPGLVKPSETLSLTCTVSGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISVDTSKNQF195 SLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS >Hu_2218_VH07QVQLQESGPGLVKPSETLSLTCTVSGYSITSGYYWNWIRQPPGKGLEWIGYISYDGYNNYNPSLKNRVTISRDTSKNQF196 SLKLSSVTAADTAVYYCANYYDYEDWYFGVWGQGTTVTVSS >Hu_2218_VH08QVQLQESGPGLMKPSETLSLTCSVSGYSITSGYYWSWIRKPPGKGLEYIGYVSYDGSTYYNPSLKSRVTISVDTSKNRF197 SLKLNSVTAADTAVYYCANYYDYEDWYFGYWGQGILVTVSS >Hu_2218_VH09QVQLQESGPGLMKPSETLSLTCSVSGYSITSGYYWNWIRKPPGKGLEWIGYISYDGYNNYNPSLKSRVTISRDTSKNRF198 SLKLNSVTAADTAVYYCANYYDYEDWYFGVWGQGILVTVSS >Hu_2218_VH10EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYYWNWIRQAPGKGLEWVASISYDGYNNYNPSVKGRITISRDDSKNTF199 YLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTLVTVSS >Hu_2218_VH11EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYYWNWIRQAPGKGLEWVAYISYDGYNNYNPSVKGRITISRDTSKNTF200 YLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTLVTVSS >Hu_2218_VH12QVQLVESGGGVVQPGRSLRLSCAASGYSITSGYYWNWVRQAPGKGLEWVAYISYDGYNNYNPSVKGRFTISRDNSKNTL201 YLQMNSLRAEDTAVYYCANYYDYEDWYFGVWGQGTMVTVSS >Hu_2218_VL01EIVLTQSPATLSLSPGERATLSCRASESVSIIGTNSIHWYQQKPGQAPRLLIYHASNLETGIPARFSGSGPGTDFTLTI202 SSLEPEDFAVYYCLQSRKIPYTFGQGTKLEIK >Hu_2218_VL02DIVLTQSPASLAVSPGQRATITCRASESVSIIGTNSIHWYQQKPGQPPKLLIYHASNLETGVPARFSGSGSGTDFTLTI203 NPVEANDTANYYCLQSRKIPYTFGGGTKLEIK >Hu_2218_VL03EIVMTQSPATLSVSPGERATLSCRASESVSIIGTNSLHWYQQKPGQAPRLLIYHASQSISGIPARFSGSGSGTEFTLTI204 SSLQSEDFAVYYCQQSRKIPYTFGGGTKVEIK >Hu_2218_VL04EIVMTQSPATLSVSPGERATLSCRASESVSIIGTNSIHWYQQKPGQAPRLLIYHASNLETGIPARFSGSGSRTEFTLTI205 SSLQSEDFAVYYCLQSRKIPYTFGGGTKVEIK >Hu_2218_VL05DIQLTQSPSSLSASVGDRVTITCRASESVSIIGTNSMNWYQQKPGKAPKLLIYHASYLESGVPSRFSGSGSGTDFTLTI206 SSLQPEDFATYYCLQSRKIPYTFGQGTKVEIK >Hu_2218_VL06DIQLTQSPSSLSASVGDRVTITCRASESVSIIGTNSMHWYQQKPGKAPKLLIYHASNLESGVPSRFSGSGSRTDFTLTI207 SSLQPEDFATYYCLQSRKIPYTFGQGTKVEIK >Hu_2218_VL07DIQMTQSPSSLSASVGDRVTITCRASESVSIIGTNSMHWYQQKPGKAPKLLIYHASNLESGVPSRFSGSGSGTDFTFTI208 SSLQPEDIATYYCLQSRKIPYTFGQGTKVEIK >Hu_2419_VH01QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYTIHWVRQAPGQGLEWMGWIYPLRGSINYNEKFKDRVTSTRDTSISTA209 YMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VH02QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGRIYPLRGSTNYAQKFQGRVTSTRDTSISTA210 YMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VH03QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYTIHWVRQAPGQGLEWMGWIYPLRGSINYNEKFKDRVTMTADTSSSTA211 YMELSRLRSDDTVVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VH04QVQLVQSGAEVKKPGASVKVSCEASGYTFTDYTIHWVRQAPGKGLEWMGWIYPLRGSINYNEKFKDRVTMTADTSTDTA212 YMELSSLRSKDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VH05QVQLVQSGAEVVKPGASVKLSCKASGYTFTDYTMYWVKQAPGQGLEWIGEIYPLRGSINFNEKFKSKATLTVDKSASTA213 YMELSSLRSEDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VH06QVQLVQSGAEVVKPGASVKLSCKASGYTFTDYTMHWVKQAPGQGLEWIGEIYPLRGSINFNEKFKSKATLTVDKSASTA214 YMELSSLRSEDTAVYYCARHGAYYSNAFDYWGQGTLVTVSS >Hu_2419_VL01EIVLTQSPATLSLSPGERATLSCRASESVDNDGIRFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGPGTDFTLTI215 SSLEPEDFAVYYCQQSNKDPYTFGQGTKLEIK >Hu_2419_VL02EIVLTQSPATLSLSPGERATLSCRASESVDNDGIRFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGPGTDFTLTI216 SSLEPEDVAVYYCQQSNKDPYTFGQGTKLEIK >Hu_2419_VL03DIVMTQSPASLAVSLGERATINCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPDRFSGSGSRTDFTLTI217 SSLQAEDVAVYYCQQSNKDPYTFGGGTKVEIK >Hu_2419_VL04DIVMTQSPASLAVSLGERATINCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPDRFSGSGSRTDFTLTI218 NSLQAEDVAVYYCQQSNKDPYTFGGGTKVELK >Hu_2419_VL05DIVLTQSPATLSVSPGERATISCRASESVDNDGIRFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTI219 SSVEPEDFATYYCQHSWEIPPTFGGGTKLEIK >hu_4035_VH01QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVAVIWSDGSTDYNAAFISRFTISRDNSKNTLY220 LQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH02QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVGVIWSDGSTDYNAAFISRFTISKDNSKNTLY221 LQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH03QVQLVESGGGVVQPGRSLRLSCAASGFSLTIYDVHWVRQAPGKGLEWVAVIWSDGSTDYADSVKGRFTISKDNSKNTLY222 LQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH04QVQLVESGGGVVQPGRSLRLSCAVSGFSLTIYDVHWVRQAPGKGLEWVGVIWSDGSTDYADSVKGRFTISKDNSKNTVY223 LQMNSLRAEDTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH05QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNAAFISRVTISVDTSKNQFS224 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH06QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQVS225 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH07QVQLQESGPGLMKPSETLSLTCSVSGDSITIYDWHWIRQPPGKGLEWIGVVWSDGSTDYNPSLKSRVTISVDTSKNRFS226 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH07QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDNSKNQFS227 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH09QVQLQESGPGLVKPSETLSLTCTVSGFSLTIYDVHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQVS262 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH10QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISKDTSKNQFS263 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH11QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWVRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISVDTSKNQFS264 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VH12QVQLQESGPGLVKPSETLSLTCTVSGGSITIYDWHWIRQPPGKGLEWIGVIWSDGSTDYNPSLKSRVTISVDTSKNQFS265 LKLSSVTAADTAVYYCARNWVDQAWFAYWGQGTLVTVSS >hu_4035_VL01DIQMTQSPSSLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKTLPEGVPSRFSGSGSGTDFTLTISSLQ228 PEDFATYYCQHHYGTPLTFGQGTKLEIK >hu_4035_VL02DIQMTQSPSSLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLVYNAKTLPEGVPSRFSGSGSGTDFTLTISSLQ229 PEDFATYYCQHHYGTPLTFGQGTKLEIK >hu_4035_VL03EIVLTQSPATLSLSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLIYNAKTRATGIPARFSGSGSGTDFTLTISSLE230 PEDFAVYYCQHHYGTPLTFGQGTKLEIK >hu_4035_VL04EIVLTQSPATLSLSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLVYNAKTLPEGIPARFSGSGSGTDFTLTISSLE231 PEDFAVYYCQHHYGTPLTFGQGTKLEIK >hu_4035_VL05EIVMTQSPATLSVSPGERATLSCRASKNIYSYLAWYQQKPGQAPRLLIYNAKTRATGIPARFSGSGSGTEFTLTISSLQ232 SEDFAVYYCQHHYGTPLTFGGGTKVEIK >hu_4035_VL06DIQLTQSPSFLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKSLQSGVPSRFSGSGSGTEFTLTISSLQ233 PEDFATYYCQHHYGTPLTFGGGTKLEIK >hu_4035_VL07DIQLTQSPSFLSASVGDRVTITCRASKNIYSYLAWYQQKPGKAPKLLIYNAKSLQSGVPSRFSGSGSGTEFTLTISSLQ234 PEDFATYYCQHHYGTPLTFGGGTKLEIK >hu_4237_VH01QLQLQESGSGLVKPSQTLSLTCAVSGFSLTDYDVHWVRQPPGKGLEWIGVIWNDGSTDYNPSLISRVTISKDNSKNQVS235 LKLSSVTAADTAVYYCARNWYGGYWFAYWGQGTLVTVSS >hu_4237_VH02QLQLQESGSGLVKPSQTLSLTCAVSGGSITDYDWHWVRQPPGKGLEWIGVIWNDGSTDYNPSLISRVTISVDNSKNQFS236 LKLSSVTAADTAVYYCARNWYGGYWFAYWGQGTLVTVSS >hu_4237_VH03QVQLVESGGGVVQPGRSLRLSCAASGESETDYDMHWVRQAPGKGLEWVAVIWNDGSTDYATSVIGRFTISRDNSKNTLY237 LQMNSLRAEDTAVYYCARNWYGGYWFAYWGQGTLVTVSS >hu_4237_VH04QVQLVESGGGVVQPGRSLRLSCAASGESETDYDMHWVRQAPGKGLEWVGVIWNDGSTDYATSVIGRFTISRDNSKNTLY238 LQMNSLRAEDTAVYYCARNWYGGYWFAYWGQGTLVTVSS >hu_4237_VH05QVQLQESGPGLMKPSETLSLTCSVSGGSITDYDWHWIRQPPGKGLEWIGVVWNDGSTDYNPSLKSRVTISVDTSKNRFS239 LKLNSVTAADTAVYYCARNWYGGYWFAYWGQGILVTVSS >hu_4237_VH06QVTLKESGPALVKPTQTLTLTCTFSGESLTDYDVHWIRQPPGKALEWLAVIWNDGSTDYSPSLKSRLTITKDTSKNQVV240 LTMTNMDPVDTATYYCARNWYGGYWFAYWGQGTLVTVSS >hu_4237_VL01DIQMTQSPSSLSASVGDRVTITCRSSENTYSYLAWYQQKPGKAPKLLVYNANALAEGVPSRFSGSGSVTDFTLTISSLQ241 PEDFATYYCQHHYGTPFTFGQGTKLEIK >hu_4237_VL02DIQMTQSPSTLSASVGDRVTITCRSSENTYSYLAWYQQKPGKAPKLLVYNANALAEGVPSRFSGSGSVTEFTLTISSLQ242 PDDFATYYCQHHYGTPFTFGQGTKLEIK >hu_4237_VL03EIVMTQSPATLSVSPGERATLSCRASENIYSYLAWYQQKPGQAPRLLIYNANASAEGIPARFSGSGSGTEFTLTISSLQ243 SEDFAVYYCQQHYGTPFTEGGGTKVEIK >hu_4237_VL04DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLLYNANRLESGVPSRFSGSGSGTDFTLTISSLQ244 PEDFASYYCQHHYGTPFTFGSGTKLEIK >hu_4237_VL05DIQMTQSPSSLSASVGDRVTITCRASENIYSYLAWYQQKPGKAPKLLLYNANRLESGVPSRFSGSGSGTDYTLTISSLQ245 PEDFASYYCQHHYGTPFTFGSGTKLEIK >hu_3833_VH01QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYNEKFKGRVTMTADTST246 STAYMELRSLRSDDTAVYYCSRSETGRAMDYWGQGTLVTVSS >hu_3833_VH02QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYAQKLQGRVTMTADTST247 STAYMELRSLRSDDTAVYYCSRSETGRAMDYWGQGTLVTVSS >hu_3833_VH03QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYAQKFQGRVTMTADTST248 STAYMELSSLRSEDTAVYYCSRSETGRAMDYWGQGTLVTVSS >hu_3833_VH04QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIGWVRQAPGQGLEWMGDIYPGGIGGGYTKYNEKFKGRVTMTADTST249 STAYMELSSLRSEDTAVYFCSRSETGRAMDYWGQGTLVTVSS >hu_3833_VH05QVQLVQSGAELKRPGASVKVSCKASGYTFTNYWMGWVKQAPGQGLEWMGDIYPGGIGGGYTNYAQKFKGKATMTADTSS250 STAYMQLSRLRSEDTAVYYCSRSETGRAMDYWGQGTLVTVSS >hu_3833_VL01DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQQKPGKAPKLLIHYTSTLKPGVPSRFSGSGSGTDFTFTISSLQ251 PEDIATYYCLQYDNLNTFGGGTKLEIK >hu_3833_VL02DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQQKPGKAPKLLIHYTSTLKPGVPSRFSGSGSGRDYTFTISSLQ252 PEDIATYYCLQYDNLNTFGGGTKLEIK >hu_3833_VL03DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQQKPGKAPKLLIYYTSTLETGVPSRFSGSGSGTDFTESISSLQ253 PEDIATYYCLQYDNLNTFGGGTKLEIK >hu_4540_VH01QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGKGLEWMGWIFPGSGSTYYNEKFKGRVTMTVDKSTSTA254 YMELSSLRSEDTAVYFCARGDSGRAMDYWGQGTLVTVSS >hu_4540_VH02QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYMNWVRQAPGQGLEWMGWIFPGSGSTYYAEKFKGRVTSTRDTSISTA255 YMELSRLRSDDTVVYYCARGDSGRAMDYWGQGTLVTVSS >hu_4540_VH03QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGQGLEWMGWIFPGSGSTYYAQKLQGRVTMTTDTSTSTA256 YMELRSLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS >hu_4540_VH04QVQLVQSGAEVKKPGASVKVSCKASGYTFADYYINWVRQAPGQGLEWMGWIFPGSGSTYYAQKLQGRVTMTVDKSSSTA257 YMELRSLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS >hu_4540_VH05QVQLVQSGAELKKPGASVKVSCKASGYTFADYYMNWVRQAPGQGLEWMGWIFPGSGSTYYNQKFQGRVTMTVDKSSSTA258 YMELSRLRSDDTAVYYCARGDSGRAMDYWGQGTLVTVSS >hu_4540_VL01DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQQKPGKAPKLLIHYTSTLQSGVPSRFSGSGSGTDFTFTISSLQ259 PEDIATYYCLQYDNLLTFGQGTKLEIK >hu_4540_VL02DIQMTQSPSSLSASVGDRVTITCKASQDINKYIAWYQHKPGKAPKLLIHYTSTLQSGVPSRFSGSGSGRDYTFTISSLQ260 PEDIATYYCLQYDNLLTFGQGTKLEIK >hu_4540_VL03DIQMTQSPSSLSASVGDRVTITCQASQDINKYLAWYQHKPGKAPKLLIHYTSTLETGVPSRFSGSGSGTDFTFTISSLQ261 PEDIATYYCLQYDNLLTFGGGTKVEIK

In an embodiment, the antibody molecule comprises one, two, or threeCDRs of the VH region of an antibody molecule described herein, e.g., inTable 1 or 5 (e.g., any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or 4237),using the Kabat or Chothia definitions of CDRs. In an embodiment, theantibody molecule comprises one, two, or three CDRs of the VL region ofan antibody molecule described herein, e.g., in Table 1 or 5 (e.g., anyof monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206,2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205,2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530,3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540,4540-063, 4540-033, 4439, 4439, or 4237), using the Kabat or Chothiadefinitions of CDRs. In an embodiment, the antibody molecule comprisesone or more (e.g., two or three) CDRs of the VH region and/or one ormore (e.g., two or three) CDRs of the VL region of an antibody moleculedescribed herein, e.g., in Table 1 or 5 (e.g., any of monoclonalantibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406,2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210,2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525,3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540,4540-063, 4540-033, 4439, 4439, or 4237), using the Kabat or Chothiadefinitions of CDRs.

In an embodiment, the antibody molecule comprises one, two, or three VHCDRs described in Table 1 or 5. In an embodiment, the antibody moleculecomprises one, two, or three VL CDRs described in Table 1 or 5. In anembodiment, the antibody molecule comprises one or more (e.g., two orthree) VH CDRs and/or one or more (e.g., two or three) VL CDRs describedin Table 1 or 5.

In an embodiment, the antibody molecule comprises one, two, three, orfour frameworks of the VH region of an antibody molecule described inTable 1 or 5 (e.g., any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or 4237).In an embodiment, the antibody molecule comprises one, two, three, orfour frameworks of the VL region of an antibody molecule described inTable 1 or 5 (e.g., any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or 4237).In an embodiment, the antibody molecule comprises one or more (e.g.,two, three, or four) frameworks of the VH region and/or one or more(e.g., two, three, or four) frameworks of the VL region of an antibodymolecule described in Table 1 or 5 (e.g., any of monoclonal antibodies2218, 2419, 2419-0105, 2419-0205, 2419-0206, 2419-0406, 2419-0605,2419-0805, 2419-0806, 2419-1204, 2419-1205, 2419-1210, 2419-1305,2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530, 3525, 3125, 2621,4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033,4439, 4439, or 4237).

In an embodiment, the antibody molecule comprises a heavy chain variableregion of an antibody molecule described herein, e.g., in Table 1 or 5(e.g., any of monoclonal antibodies 2218, 2419, 2419-0105, 2419-0205,2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204,2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922,3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732,4338, 4540, 4540-063, 4540-033, 4439, 4439, or 4237). In an embodiment,the antibody molecule comprises a light chain variable region of anantibody molecule described herein, e.g., in Table 1 or 5 (e.g., any ofmonoclonal antibodies 2218, 2419, 2419-0105, 2419-0205, 2419-0206,2419-0406, 2419-0605, 2419-0805, 2419-0806, 2419-1204, 2419-1205,2419-1210, 2419-1305, 2419-1306, 2419-1310, 2419-1406, 2922, 3327, 3530,3525, 3125, 2621, 4035, 4035-062, 3934, 3833, 3631, 3732, 4338, 4540,4540-063, 4540-033, 4439, 4439, or 4237). In an embodiment, the antibodymolecule comprises a heavy chain variable region and a light chainvariable region of an antibody molecule described herein, e.g., in Table1 or 5 (e.g., any of monoclonal antibodies 2218, 2419, 2419-0105,2419-0205, 2419-0206, 2419-0406, 2419-0605, 2419-0805, 2419-0806,2419-1204, 2419-1205, 2419-1210, 2419-1305, 2419-1306, 2419-1310,2419-1406, 2922, 3327, 3530, 3525, 3125, 2621, 4035, 4035-062, 3934,3833, 3631, 3732, 4338, 4540, 4540-063, 4540-033, 4439, 4439, or 4237).

In an embodiment, the antibody molecule comprises a heavy chain variableregion having an amino acid sequence described in Table 1 or 5, or anamino acid sequence substantially identical thereof. In an embodiment,the antibody molecule comprises a light chain variable region having anamino acid sequence described in Table 1 or 5, or an amino acid sequencesubstantially identical thereof. In an embodiment, the antibody moleculecomprises a heavy chain variable region having an amino acid sequencedescribed in Table 1 or 5 (or an amino acid sequence substantiallyidentical thereof) and a light chain variable region having an aminoacid sequences described in Table 1 or 5 (or an amino acid sequencesubstantially identical thereof).

In an embodiment, the antibody molecule comprises a heavy chain variableregion encoded by a nucleotide sequence described in Table 2, or anucleotide sequence substantially identical thereof. In an embodiment,the antibody molecule comprises a light chain variable region encoded bya nucleotide sequence described in Table 2, or a nucleotide sequencesubstantially identical thereof. In an embodiment, the antibody moleculecomprises a heavy chain variable region encoded by a nucleotide sequencedescribed in Table 2 (or a nucleotide sequence substantially identicalthereof) and a light chain variable region encoded by a nucleotidesequence described in Table 2 (or a nucleotide sequence substantiallyidentical thereof).

In an embodiment, the antibody molecule further comprises a heavy chainconstant region. In an embodiment, the heavy chain constant region is anIgG1 constant region, e.g., any of SEQ ID NOS: 320-322, or a functionalportion thereof. In another embodiment, the heavy chain constant regionis an IgG2 constant region, e.g., any of SEQ ID NOS: 323-326, or afunctional portion thereof. In an embodiment, the antibody moleculefurther comprises a light chain constant region. In an embodiment, theantibody molecule further comprises a heavy chain constant region and alight chain constant region. In an embodiment, the antibody moleculecomprises a heavy chain constant region, a light chain constant region,and heavy and light chain variable regions of an antibody moleculedescribed in Table 1 or 5. In certain embodiments, the antibody moleculecomprises a heavy chain constant region, a light chain constant region,and variable regions that comprise one, two, three, four, five, or sixCDRs of an antibody molecule described in Table 1 or 5.

Exemplary heavy chain constant regions are described below.

Exemplary IgG1 Constant Regions

>IGHG1*01 (SEQ ID NO: 320)STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP >IGHG1*03 (SEQ ID NO: 321)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP >IGHG1*04(SEQ ID NO: 322) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNHYTQKSLSLSP 

Exemplary IgG2 Constant Regions

>IGHG2*01 (SEQ ID NO: 323)STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP >IGHG2*02 (SEQ ID NO: 324)STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP >IGHG2*04 (SEQ ID NO: 325)STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP >IGHG2*06 (SEQ ID NO: 326)STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 11; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 12; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of SEQ ID NO: 280; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the SEQ ID NO: 285; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of theLCDR1 of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 285; or an LCDR3 comprising the amino acid sequence of SEQ IDNO: 16.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 17; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 282; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the SEQ ID NO: 285; or an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of SEQ IDNO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285;or an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises a VH comprising theamino acid sequence of SEQ ID NO: 296. In an embodiment, the antibodymolecule comprises a VL comprising the amino acid sequence of SEQ ID NO:286. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of SEQ ID NO: 296 and a VL comprising the aminoacid sequence of SEQ ID NO: 286.

In an embodiment, the antibody molecule comprises a VH encoded by anucleic acid comprising the nucleotide sequence of SEQ ID NO: 313. In anembodiment, the antibody molecule comprises a VL encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 306. In anembodiment, the antibody molecule comprises a VH encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 313 and a VLencoded by a nucleic acid comprising the nucleotide sequence of SEQ IDNO: 306.

In an embodiment, the antibody molecule further comprises a heavyconstant region of IgG2, e.g., any of SEQ ID NOS: 323-326.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 11; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 12; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of SEQ ID NO: 280; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the SEQ ID NO: 285; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of theLCDR1 of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 285; or an LCDR3 comprising the amino acid sequence of SEQ IDNO: 16.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 17; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 282; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the SEQ ID NO: 285; or an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of SEQ IDNO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 285;or an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises a VH comprising theamino acid sequence of SEQ ID NO: 289. In an embodiment, the antibodymolecule comprises a VL comprising the amino acid sequence of SEQ ID NO:286. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of SEQ ID NO: 289 and a VL comprising the aminoacid sequence of SEQ ID NO: 286.

In an embodiment, the antibody molecule comprises a VH encoded by anucleic acid comprising the nucleotide sequence of SEQ ID NO: 308. In anembodiment, the antibody molecule comprises a VL encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 305. In anembodiment, the antibody molecule comprises a VH encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 308 and a VLencoded by a nucleic acid comprising the nucleotide sequence of SEQ IDNO: 306.

In an embodiment, the antibody molecule further comprises a heavyconstant region of IgG2, e.g., any of SEQ ID NOS: 323-326.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 11; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 12; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of SEQ ID NO: 280; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the SEQ ID NO: 281; or anLCDR3 comprising an amino acid sequence that differs by no more than 1,2, or 3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of theLCDR1 of SEQ ID NO: 280; an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 281; or an LCDR3 comprising the amino acid sequence of SEQ IDNO: 16.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 17; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 282; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 13, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of SEQ ID NO: 280; an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the SEQ ID NO: 281; or an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 17;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 282; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of SEQ IDNO: 280; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 281;or an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.

In an embodiment, the antibody molecule comprises a VH comprising theamino acid sequence of SEQ ID NO: 289. In an embodiment, the antibodymolecule comprises a VL comprising the amino acid sequence of SEQ ID NO:284. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of SEQ ID NO: 289 and a VL comprising the aminoacid sequence of SEQ ID NO: 284.

In an embodiment, the antibody molecule comprises a VH encoded by anucleic acid comprising the nucleotide sequence of SEQ ID NO: 308. In anembodiment, the antibody molecule comprises a VL encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 305. In anembodiment, the antibody molecule comprises a VH encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 308 and a VLencoded by a nucleic acid comprising the nucleotide sequence of SEQ IDNO: 305.

In an embodiment, the antibody molecule further comprises a heavyconstant region of IgG2, e.g., any of SEQ ID NOS: 323-326.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 93; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 94; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 95, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of the LCDR1 of SEQ ID NO: 96; an LCDR2comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of the SEQ ID NO: 97; or an LCDR3comprising an amino acid sequence that differs by no more than 1, 2, or3 amino acid residues from, or has at least 85, 90, 95, 99 or 100%homology with, the amino acid sequence of SEQ ID NO: 98.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 93;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 94; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 95, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of theLCDR1 of SEQ ID NO: 96; an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 97; or an LCDR3 comprising the amino acid sequence of SEQ IDNO: 98.

In an embodiment, the antibody molecule comprises one or both of:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises one, two, or all of the following: an HCDR1 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 99; an HCDR2 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 273; or an HCDR3 comprising an amino acidsequence that differs by no more than 1, 2, or 3 amino acid residuesfrom, or has at least 85, 90, 95, 99 or 100% homology with, the aminoacid sequence of SEQ ID NO: 95, or

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises one, two, or all of the following: an LCDR1 comprisingan amino acid sequence that differs by no more than 1, 2, or 3 aminoacid residues from, or has at least 85, 90, 95, 99 or 100% homologywith, the amino acid sequence of SEQ ID NO: 96; an LCDR2 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of the SEQ ID NO: 97; or an LCDR3 comprising anamino acid sequence that differs by no more than 1, 2, or 3 amino acidresidues from, or has at least 85, 90, 95, 99 or 100% homology with, theamino acid sequence of SEQ ID NO: 98.

In an embodiment, the antibody molecule comprises:

(i) a heavy chain variable region (VH), wherein the heavy chain variableregion comprises three heavy chain complementarity determining regions(HCDR1, HCDR2, and HCDR3), wherein the heavy chain variable regioncomprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 99;an HCDR2 comprising the amino acid sequence of SEQ ID NO: 273; and anHCDR3 comprising the amino acid sequence of SEQ ID NO: 95, and

(ii) a light chain variable region (VL), wherein the light chainvariable region comprises three light chain complementarity determiningregions (LCDR1, LCDR2, and LCDR3), wherein the light chain variableregion comprises: an LCDR1 comprising the amino acid sequence of SEQ IDNO: 96; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 97; oran LCDR3 comprising the amino acid sequence of SEQ ID NO: 98.

In an embodiment, the antibody molecule comprises a VH comprising theamino acid sequence of SEQ ID NO: 225. In an embodiment, the antibodymolecule comprises a VL comprising the amino acid sequence of SEQ ID NO:229. In an embodiment, the antibody molecule comprises a VH comprisingthe amino acid sequence of SEQ ID NO: 225 and a VL comprising the aminoacid sequence of SEQ ID NO: 229.

In an embodiment, the antibody molecule comprises a VH encoded by anucleic acid comprising the nucleotide sequence of SEQ ID NO: 299. In anembodiment, the antibody molecule comprises a VL encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 300. In anembodiment, the antibody molecule comprises a VH encoded by a nucleicacid comprising the nucleotide sequence of SEQ ID NO: 299 and a VLencoded by a nucleic acid comprising the nucleotide sequence of SEQ IDNO: 300.

In an embodiment, the antibody molecule further comprises a heavy chainconstant region of IgG1, e.g., any of SEQ ID NOS: 320-322.

In an embodiment, the antibody molecule described herein has one or more(e.g., 2, 3, 4, 5, or all) of the following properties: (a) is ahumanized antibody molecule; (b) binds to human APRIL at an EC₅₀ of 60pM or less, as determined by ELISA; (c) inhibits binding of human APRILto TACI, e.g., in vitro, at an IC₅₀ of 0.5 nM or less; (d) inhibitsbinding of human APRIL to BCMI, e.g., in vitro, at an IC₅₀ of 0.6 nM orless; (e) is an IgG2K; or (f) has an Fc region engineered to reducecomplement activation. In an embodiment, the antibody molecule comprisesone or more (e.g., 2, 3, 4, 5, or all) CDRs, one or both of heavy chainvariable region or light chain variable regions, or one or both of heavychain or light chain, of any of antibody molecules 2419-1406, 2419-0205,or 2419-0206. In an embodiment, the antibody molecule is suitable foruse in treating a disorder in kidney, e.g., IgA nephropathy. In anotherembodiment, the antibody molecule is suitable for use in treating acancer, e.g., a multiple myeloma.

In an embodiment, the antibody molecule described herein has one or more(e.g., 2, 3, 4, 5, or all) of the following properties: (a) is ahumanized antibody molecule; (b) binds to human APRIL at an EC₅₀ of 50pM or less, as determined by ELISA; (c) inhibits binding of human APRILto TACI, e.g., in vitro, at an IC₅₀ of 0.3 nM or less; (d) inhibitsbinding of human APRIL to BCMA, e.g., in vitro, at an IC₅₀ of 0.2 nM orless; (e) is an IgG1κ; or (f) has higher BCMA neutralization activity,e.g., has an IC₅₀ of 0.1 nM or less. In an embodiment, the antibodymolecule comprises one or more (e.g., 2, 3, 4, 5, or all) CDRs, one orboth of heavy chain variable region or light chain variable regions, orone or both of heavy chain or light chain, of antibody molecule4035-062. In an embodiment, the antibody molecule is suitable for use intreating a cancer or an autoimmune disorder.

The antibody molecules described herein can have several advantageousproperties. For example, the antibody molecules can be used toeffectively treat, prevent or diagnose a disorder associated with APRIL,e.g., a disorder described herein, e.g., IgA nephropathy.

In an embodiment, the antibody molecule is capable of binding, orsubstantially binding, to human APRIL and mouse APRIL. In an embodiment,the antibody molecule is capable of binding, or substantially binding,to human APRIL, but is not capable of binding, or substantially bindingto mouse APRIL. In an embodiment, the antibody molecule binds to APRILwith high affinity, e.g., with a dissociation constant (K_(D)) of lessthan about 100 nM, typically about 10 nM, and more typically, about10-0.001 nM, about 10-0.01 nM, about 10-0.01 nM, about 5-0.01 nM, about3-0.05 nM, about 1-0.1 nM, or stronger, e.g., less than about 80, 70,60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01,0.005, or 0.001 nM. In an embodiment, the antibody molecule binds toAPRIL with a K_(off) slower than 1×10⁻⁴, 5×10⁻⁵, or 1×10⁻⁵ s⁻¹. In anembodiment, the antibody molecule binds to APRIL with a K_(on) fasterthan 1×10⁴, 5×10⁴, 1×10⁵, or 5×10⁵ M⁻¹s⁻¹.

In an embodiment, the antibody molecule is capable of inhibiting, orsubstantially inhibiting, binding of human APRIL to TACI. In anembodiment, the antibody molecule is capable of inhibiting, orsubstantially inhibiting, binding of human APRIL to TACI. In anembodiment, the antibody molecule is capable of inhibiting, orsubstantially inhibiting, binding of human APRIL to BCMA. In anembodiment, the antibody molecule is capable of inhibiting, orsubstantially inhibiting, binding of human APRIL to TACI and BCMA. In anembodiment, the antibody molecule is capable of inhibiting, orsubstantially inhibiting, binding of human APRIL to TACI, but is notcapable of inhibiting, or substantially inhibiting, binding of humanAPRIL to BCMA. In an embodiment, the antibody molecule is capable ofinhibiting, or substantially inhibiting, binding of human APRIL to BCMA,but is not capable of inhibiting, or substantially inhibiting, bindingof human APRIL to TACI.

In an embodiment, the antibody molecule inhibits binding of human APRILto human TACI by 50% or more, e.g., 60% or more, 70% or more, 80% ormore, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more,98% or more, 99% or more, or 100%, as determined by a method describedherein (e.g., normalized to the no antibody control).

In an embodiment, the antibody molecule inhibits binding of human APRILto human BCMA by 30% or more, e.g., 40% or more, 50% or more, 60% ormore, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more,96% or more, 97% or more, 98% or more, 99% or more, or 100%, asdetermined by a method described herein (e.g., normalized to the noantibody control).

In an embodiment, the antibody molecule does not substantially inhibitbinding of human APRIL to human BCMA, e.g., inhibits binding of humanAPRIL to human BCMA by less than 10%, as determined by a methoddescribed herein (e.g., normalized to the no antibody control).

In an embodiment, the antibody molecule binds to a linear orconformational epitope on APRIL. In an embodiment, the antibody moleculebinds to an epitope conserved between human APRIL and mouse APRIL. In anembodiment, the antibody molecule binds to an epitope described herein.In an embodiment, the antibody molecule binds, or substantially binds,to the same, similar, or overlapping epitope on APRIL, as a secondantibody molecule (e.g., a monoclonal antibody described in Table 1 or5). In an embodiment, the antibody molecule competes with a secondantibody molecule (e.g., a monoclonal antibody described in Table 1 or5) for binding to APRIL.

In an embodiment, the antibody molecule binds, or substantially binds,one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within a region ofAPRIL as defined in Table 3. In an embodiment, the antibody moleculebinds, or substantially binds, to an epitope that comprises or consistsof one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRILresidues from Table 3. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that overlaps an epitope thatcomprises or consists of all of the human APRIL residues from Table 3.In an embodiment, the antibody molecule binds, or substantially binds,to an epitope that comprises APRIL residues from two monomers, e.g., oneor more residues from monomer A and monomer B as shown in Table 3.

In an embodiment, the antibody molecule binds, or substantially binds,one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, residues withina region of APRIL as defined in Table 4. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that comprises orconsists of one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of thehuman APRIL residues from Table 4. In an embodiment, the antibodymolecule binds, or substantially binds, to an epitope that overlaps anepitope that comprises or consists of all of the human APRIL residuesfrom Table 4. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that comprises one or more APRILresidues from the C-D loop (e.g., the loop connecting β-sheets C and D),the G-H loop (e.g., the loop connecting β-sheets G and H), or both.

In an embodiment, the antibody molecule binds, or substantially binds,to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all) residues of humanAPRIL from positions 105-114 and/or one or more (e.g., 2, 3, 4, 5, 6, 7,8, 9, or all) residues of mouse APRIL from positions 96-105.

In an embodiment, the antibody molecule binds, or substantially binds,one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, or more, residues within a region of APRIL as defined in Table 7. Inan embodiment, the antibody molecule binds, or substantially binds, toan epitope that comprises or consists of one or more, e.g., 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all of the human APRILresidues from Table 7. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that overlaps an epitope thatcomprises or consists of all of the human APRIL residues from Table 7.

In an embodiment, the antibody molecule binds, or substantially binds,one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, or more, residues within a region ofAPRIL as defined in Table 8. In an embodiment, the antibody moleculebinds, or substantially binds, to an epitope that comprises or consistsof one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the human APRILresidues from Table 8. In an embodiment, the antibody molecule binds, orsubstantially binds, to an epitope that overlaps an epitope thatcomprises or consists of all of the human APRIL residues from Table 8.

In an embodiment, the epitope is a conformational epitope.

In an embodiment, the antibody molecule does not bind, or does notsubstantially bind, to one, two or all of Asp129, Arg233, or His203 ofhuman APRIL.

In an embodiment, binding of the antibody molecule to APRIL (e.g., humanAPRIL) inhibits, or substantially inhibits, the binding of the CRD2domain of TACI (e.g., human TACI) to APRIL (e.g., human APRIL). Inanother embodiment, binding of the antibody molecule to human APRIL,inhibits, or substantially inhibits, the binding of human TACI, to oneor more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, or all of the APRIL residues from Table3. In yet another embodiment, binding of the antibody molecule to humanAPRIL, inhibits, or substantially inhibits, the binding of human TACI,to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the humanAPRIL residues from Table 4. In still another embodiment, binding of theantibody molecule to human APRIL, inhibits, or substantially inhibits,the binding of human TACI, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, or all of the human APRIL residues fromTable 7. In still another embodiment, binding of the antibody moleculeto human APRIL, inhibits, or substantially inhibits, the binding ofhuman TACI, to one or more, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all of the humanAPRIL residues from Table 8.

Animal Models

The antibody molecules described herein can be evaluated in vivo, e.g.,using various animal models. For example, an animal model can be used totest the efficacy of an antibody molecule described herein in inhibitingAPRIL and/or in treating or preventing a disorder described herein,e.g., IgA nephropathy. Animal models can also be used, e.g., toinvestigate for side effects, measure concentrations of antibodymolecules in situ, demonstrate correlations between an APRIL functionand a disorder described herein (e.g., IgA nephropathy).

Exemplary animal models for IgA nephropathy that can be used forevaluating an antibody molecule described herein include, but are notlimited to, a ddY mouse model for spontaneous IgA nephritis (Imai et al.Kidney Int. 1985; 27(5):756-761); a mouse model utilizing inert proteinsor a common viral pathogen as the inciting antigen (Emancipator et al.Curr. Protoc. Immunol. 2001 May; Chapter 15: Unit 15.11), a rat model bynoninfectious protein antigens (Emancipator et al. Curr. Protoc.Immunol. 2001 May; Chapter 15: Unit 15.11); a chronic mouse model of IgAimmune-complex-associated nephropathy (Montinaro et al. Nephrol. Dial.Transplant. 1995; 10(11): 2035-2042); the Gne M712T mouse as a model forhuman glomerulopathy (Kakani et al. Am. J. Pathol. 2012;180(4):1431-1440); a mouse IgA nephropathy model with the MBP-20-peptidefusion protein (Zhang et al. Anat. Rec. (Hoboken). 2010; 293(10):1729-1737); and a mouse model for IgA immune complex nephritis (Rifai etal. J Exp Med. 1979; 150(5):1161-1173). Other animal models for IgAnephropathy are described, e.g., in Tomino et al. J. Nephrol. 2008;21(4):463-467; Endo Ren. Fail. 1997; 19(3):347-371; and Rifai KidneyInt. 1987; 31(1):1-7.

Exemplary animal models for other disorders described herein are alsoknown in the art. Exemplary types of animals that can be used toevaluate the antibody molecules described herein include, but are notlimited to, mice, rats, rabbits, guinea pigs, and monkeys.

Pharmaceutical Compositions and Kits

In some aspects, this disclosure provides compositions, e.g.,pharmaceutically acceptable compositions, which include an antibodymolecule described herein (e.g., a humanized antibody molecule describedherein), formulated together with a pharmaceutically acceptable carrier.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, isotonic and absorption delaying agents,and the like that are physiologically compatible. The carrier can besuitable for intravenous, intramuscular, subcutaneous, parenteral,rectal, spinal or epidermal administration (e.g., by injection orinfusion). In certain embodiments, less than about 5%, e.g., less thanabout 4%, 3%, 2%, or 1% of the antibody molecules in the pharmaceuticalcomposition are present as aggregates. In other embodiments, at leastabout 95%, e.g., at least about 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.8%,or more of the antibody molecules in the pharmaceutical composition arepresent as monomers. In some embodiments, the level of aggregates ormonomers is determined by chromatography, e.g., high performance sizeexclusion chromatography (HP-SEC).

The compositions set out herein may be in a variety of forms. Theseinclude, for example, liquid, semi-solid and solid dosage forms, such asliquid solutions (e.g., injectable and infusible solutions), dispersionsor suspensions, liposomes, and suppositories. A suitable form depends onthe intended mode of administration and therapeutic application. Typicalsuitable compositions are in the form of injectable or infusiblesolutions. One suitable mode of administration is parenteral (e.g.,intravenous, subcutaneous, intraperitoneal, intramuscular). In someembodiments, the antibody molecule is administered by intravenousinfusion or injection. In certain embodiments, the antibody isadministered by intramuscular or subcutaneous injection.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, epidural and intrasternal injection andinfusion.

Therapeutic compositions typically should be sterile and stable underthe conditions of manufacture and storage. The composition can beformulated as a solution, microemulsion, dispersion, liposome, or otherordered structure suitable to high antibody concentration. Sterileinjectable solutions can be prepared by incorporating the activecompound (i.e., antibody or antibody portion) in the required amount inan appropriate solvent with one or a combination of ingredientsenumerated above, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the active compoundinto a sterile vehicle that contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.The proper fluidity of a solution can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prolonged absorption of injectable compositions can be brought about byincluding in the composition an agent that delays absorption, forexample, monostearate salts and gelatin.

The antibody molecules described herein can be administered by a varietyof methods. Several are known in the art, and for many therapeutic,prophylactic, or diagnostic applications, an appropriate route/mode ofadministration is intravenous injection or infusion. For example, theantibody molecules can be administered by intravenous infusion at a rateof less than 10 mg/min; preferably less than or equal to 5 mg/min toreach a dose of about 1 to 100 mg/m², preferably about 5 to 50 mg/m²,about 7 to 25 mg/m² and more preferably, about 10 mg/m². As will beappreciated by the skilled artisan, the route and/or mode ofadministration will vary depending upon the desired results. In certainembodiments, the active compound may be prepared with a carrier thatwill protect the compound against rapid release, such as a controlledrelease formulation, including implants, transdermal patches, andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Manymethods for the preparation of such formulations are patented orgenerally known to those skilled in the art. See, e.g., Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978.

In certain embodiments, an antibody molecule can be orally administered,for example, with an inert diluent or an assimilable edible carrier. Theantibody molecule (and other ingredients, if desired) may also beenclosed in a hard or soft shell gelatin capsule, compressed intotablets, or incorporated directly into the subject's diet. For oraltherapeutic administration, the antibody molecule may be incorporatedwith excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. To administer an antibody molecule by other than parenteraladministration, it may be necessary to coat the compound with, orco-administer the compound with, a material to prevent its inactivation.Therapeutic, prophylactic, or diagnostic compositions can also beadministered with medical devices, and several are known in the art.

Dosage regimens are adjusted to provide the desired response (e.g., atherapeutic, prophylactic, or diagnostic response). For example, asingle bolus may be administered, several divided doses may beadministered over time or the dose may be proportionally reduced orincreased as indicated by the exigencies of the therapeutic situation.It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontains a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe antibody molecule and the particular therapeutic, prophylactic, ordiagnostic effect to be achieved, and (b) the limitations inherent inthe art of compounding such an antibody molecule for the treatment ofsensitivity in individuals.

An exemplary, non-limiting range for a therapeutically,prophylactically, or diagnostically effective amount of an antibodymolecule is about 0.1-50 mg/kg body weight of a subject, e.g., about0.1-30 mg/kg, e.g., about 1-30, 1-15, 1-10, 1-5, 5-10, or 1-3 mg/kg,e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 mg/kg.The antibody molecule can be administered by intravenous infusion at arate of less than 10 mg/min, e.g., less than or equal to 5 mg/min toreach a dose of about 1 to 100 mg/m², e.g., about 5 to 50 mg/m², about 7to 25 mg/m², e.g., about 10 mg/m². It is to be noted that dosage valuesmay vary with the type and severity of the condition to be alleviated.It is to be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that dosageranges set forth herein are exemplary only and are not intended to limitthe scope or practice of the claimed compositions.

The pharmaceutical compositions herein may include a “therapeuticallyeffective amount,” “prophylactically effective amount,” or“diagnostically effectively amount” of an antibody molecule describedherein.

A “therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of the antibodymolecule may vary according to factors such as the disease state, age,sex, and weight of the individual, and the ability of the antibody orantibody portion to elicit a desired response in the individual. Atherapeutically effective amount is also one in which any toxic ordetrimental effect of the antibody molecule is outweighed by thetherapeutically beneficial effects. A “therapeutically effective dosage”typically inhibits a measurable parameter by at least about 20%, e.g.,by at least about 40%, by at least about 60%, or by at least about 80%relative to untreated subjects. The measurable parameter may be, e.g.,hematuria, colored urine, foamy urine, pain, swelling (edema) in thehands and feet, or high blood pressure. The ability of an antibodymolecule to inhibit a measurable parameter can be evaluated in an animalmodel system predictive of efficacy in treating or preventing IgAnephropathy. Alternatively, this property of a composition can beevaluated by examining the ability of the antibody molecule to inhibitAPRIL, e.g., by an in vitro assay.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

A “diagnostically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desireddiagnostic result. Typically, a diagnostically effective amount is onein which a disorder, e.g., a disorder described herein, e.g., IgAnephropathy, can be diagnosed in vitro, ex vivo, or in vivo.

Also within this disclosure is a kit that comprises an antibodymolecule, described herein. The kit can include one or more otherelements including: instructions for use; other reagents, e.g., a label,a therapeutic agent, or an agent useful for chelating, or otherwisecoupling, an antibody molecule to a label or therapeutic agent, or aradioprotective composition; devices or other materials for preparingthe antibody molecule for administration; pharmaceutically acceptablecarriers; and devices or other materials for administration to asubject.

Nucleic Acids

The present disclosure also features nucleic acids comprising nucleotidesequences that encode the antibody molecules (e.g., heavy and lightchain variable regions and CDRs of the antibody molecules), as describedherein.

For example, the present disclosure features a first and second nucleicacid encoding heavy and light chain variable regions, respectively, ofan antibody molecule chosen from one or more of the antibody moleculesdisclosed herein, e.g., an antibody molecule of Table 1 or 5, or aportion of an antibody molecule, e.g., the variable regions of Table 2.The nucleic acid can comprise a nucleotide sequence encoding any one ofthe amino acid sequences in the tables herein, or a sequencesubstantially identical thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, or which differs by no morethan 3, 6, 15, 30, or 45 nucleotides from the sequences shown in thetables herein).

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs from a heavy chainvariable region having an amino acid sequence as set forth in the tablesherein, or a sequence substantially homologous thereto (e.g., a sequenceat least about 85%, 90%, 95%, 99% or more identical thereto, and/orhaving one or more substitutions, e.g., conserved substitutions). Insome embodiments, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, or three CDRs from a light chain variableregion having an amino acid sequence as set forth in the tables herein,or a sequence substantially homologous thereto (e.g., a sequence atleast about 85%, 90%, 95%, 99% or more identical thereto, and/or havingone or more substitutions, e.g., conserved substitutions). In someembodiments, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, three, four, five, or six CDRs from heavyand light chain variable regions having an amino acid sequence as setforth in the tables herein, or a sequence substantially homologousthereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or moreidentical thereto, and/or having one or more substitutions, e.g.,conserved substitutions).

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs from a heavy chainvariable region having the nucleotide sequence as set forth in Table 2,a sequence substantially homologous thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, and/or capable ofhybridizing under the stringency conditions described herein). In someembodiments, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, or three CDRs from a light chain variableregion having the nucleotide sequence as set forth in Table 2, or asequence substantially homologous thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, and/or capable ofhybridizing under the stringency conditions described herein). Incertain embodiments, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, three, four, five, or six CDRs from heavyand light chain variable regions having the nucleotide sequence as setforth in Table 2, or a sequence substantially homologous thereto (e.g.,a sequence at least about 85%, 90%, 95%, 99% or more identical thereto,and/or capable of hybridizing under the stringency conditions describedherein).

In certain embodiments, the nucleic acid comprises a nucleotide sequenceas set forth in Table 2 or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or capable of hybridizing under the stringency conditionsdescribed herein). In some embodiments, the nucleic acid comprises aportion of a nucleotide sequence as set forth in Table 2 or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or capable of hybridizingunder the stringency conditions described herein). The portion mayencode, for example, a variable region (e.g., VH or VL); one, two, orthree or more CDRs; or one, two, three, or four or more frameworkregions.

The nucleic acids disclosed herein include deoxyribonucleotides orribonucleotides, or analogs thereof. The polynucleotide may be eithersingle-stranded or double-stranded, and if single-stranded may be thecoding strand or non-coding (antisense) strand. A polynucleotide maycomprise modified nucleotides, such as methylated nucleotides andnucleotide analogs. The sequence of nucleotides may be interrupted bynon-nucleotide components. A polynucleotide may be further modifiedafter polymerization, such as by conjugation with a labeling component.The nucleic acid may be a recombinant polynucleotide, or apolynucleotide of genomic, cDNA, semisynthetic, or synthetic originwhich either does not occur in nature or is linked to anotherpolynucleotide in a non-natural arrangement.

In some aspects, the application features host cells and vectorscontaining the nucleic acids described herein. The nucleic acids may bepresent in a single vector or separate vectors present in the same hostcell or separate host cell, as described in more detail below.

Vectors

Further provided herein are vectors that comprise nucleotide sequencesencoding an antibody molecule described herein.

In an embodiment, the vector comprises a nucleotide encoding an antibodymolecule described herein, e.g., as described in Table 1 or 5. Inanother embodiment, the vector comprises a nucleotide sequence describedherein, e.g., in Table 2. The vectors include, but are not limited to, avirus, plasmid, cosmid, lambda phage or a yeast artificial chromosome(YAC).

Numerous vector systems can be employed. For example, one class ofvectors utilizes DNA elements which are derived from animal viruses suchas, for example, bovine papilloma virus, polyoma virus, adenovirus,vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV orMOMLV) or SV40 virus. Another class of vectors utilizes RNA elementsderived from RNA viruses such as Semliki Forest virus, Eastern EquineEncephalitis virus and Flaviviruses.

Additionally, cells which have stably integrated the DNA into theirchromosomes may be selected by introducing one or more markers whichallow for the selection of transfected host cells. The marker mayprovide, for example, prototropy to an auxotrophic host, biocideresistance (e.g., antibiotics), or resistance to heavy metals such ascopper, or the like. The selectable marker gene can be either directlylinked to the DNA sequences to be expressed, or introduced into the samecell by cotransformation. Additional elements may also be needed foroptimal synthesis of mRNA. These elements may include splice signals, aswell as transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the constructs hasbeen prepared for expression, the expression vectors may be transfectedor introduced into an appropriate host cell. Various techniques may beemployed to achieve this, such as, for example, protoplast fusion,calcium phosphate precipitation, electroporation, retroviraltransduction, viral transfection, gene gun, lipid based transfection orother conventional techniques. In the case of protoplast fusion, thecells are grown in media and screened for the appropriate activity.

Methods and conditions for culturing the resulting transfected cells andfor recovering the antibody molecule produced are known to those skilledin the art, and may be varied or optimized depending upon the specificexpression vector and mammalian host cell employed, based upon thepresent description.

Cells

The present disclosure also provides cells (e.g., host cells) comprisinga nucleic acid encoding an antibody molecule as described herein. Forexample, the host cells may comprise a nucleic acid molecule having anucleotide sequence described in Table 2, a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or capable of hybridizing under thestringency conditions described herein), or a portion of one of saidnucleic acids. Additionally, the host cells may comprise a nucleic acidmolecule encoding an amino acid sequence of Table 1 or 5, a sequencesubstantially homologous thereto (e.g., a sequence at least about 80%,85%, 90%, 95%, 99% or more identical thereto), or a portion of one ofsaid sequences.

In some embodiments, the host cells are genetically engineered tocomprise nucleic acids encoding the antibody molecule described herein.

In certain embodiments, the host cells are genetically engineered byusing an expression cassette. The phrase “expression cassette,” refersto nucleotide sequences, which are capable of affecting expression of agene in hosts compatible with such sequences. Such cassettes may includea promoter, an open reading frame with or without introns, and atermination signal. Additional factors necessary or helpful in effectingexpression may also be used, such as, for example, an induciblepromoter.

The disclosure also provides host cells comprising the vectors describedherein.

The cell can be, but is not limited to, a eukaryotic cell, a bacterialcell, an insect cell, or a human cell. Suitable eukaryotic cellsinclude, but are not limited to, Vero cells, HeLa cells, COS cells, CHOcells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cellsinclude, but are not limited to, Sf9 cells. In an embodiment, the cell(e.g., host cell) is an isolated cell.

Uses of Antibody Molecules

The antibody molecules disclosed herein, as well as the pharmaceuticalcompositions disclosed herein, have in vitro, ex vivo, and in vivotherapeutic, prophylactic, and/or diagnostic utilities.

In an embodiment, the antibody molecule reduces (e.g., inhibits, blocks,or neutralizes) one or more biological activities of APRIL. For example,these antibodies molecules can be administered to cells in culture, invitro or ex vivo, or to a subject, e.g., a human subject, e.g., in vivo,to reduce (e.g., inhibits, blocks, or neutralizes) one or morebiological activities of APRIL. In an embodiment, the antibody moleculeinhibits, or substantially inhibit, binding of APRIL, e.g., human APRIL,to TACI, BCMA, or both. Accordingly, in an aspect, the disclosureprovides a method of treating, preventing, or diagnosing a disorder,e.g., a disorder described herein (e.g., IgA nephropathy), in a subject,comprising administering to the subject an antibody molecule describedherein, such that the disorder is treated, prevented, or diagnosed. Forexample, the disclosure provides a method comprising contacting theantibody molecule described herein with cells in culture, e.g. in vitroor ex vivo, or administering the antibody molecule described herein to asubject, e.g., in vivo, to treat, prevent, or diagnose a disorder, e.g.,a disorder associated with APRIL (e.g., IgA nephropathy).

As used herein, the term “subject” is intended to include human andnon-human animals. In some embodiments, the subject is a human subject,e.g., a human patient having a disorder described herein (e.g., IgAnephropathy), or at risk of having a disorder described herein (e.g.,IgA nephropathy). The term “non-human animals” includes mammals andnon-mammals, such as non-human primates. In some embodiments, thesubject is a human. The methods and compositions described herein aresuitable for treating human patients a disorder described herein (e.g.,IgA nephropathy). Patients having a disorder described herein (e.g., IgAnephropathy) include those who have developed a disorder describedherein (e.g., IgA nephropathy) but are (at least temporarily)asymptomatic, patients who have exhibited a symptom of a disorderdescribed herein (e.g., IgA nephropathy), or patients having a disorderrelated to or associated with a disorder described herein (e.g., IgAnephropathy).

Methods of Treating or Preventing Disorders

The antibody molecules described herein can be used to treat or preventdisorders associated with APRIL or symptoms thereof.

Exemplary disorders or conditions that can be associated with APRILinclude, but are not limited to IgA nephropathy, diabetic nephropathy,cancer (e.g., hematological cancer (e.g., B-cell non-Hodgkin's lymphoma,chronic lymphocytic leukemia, Hodgkin's lymphoma, multiple myeloma,Waldenström macroglobulinemia, and lymphoplasmacytic lymphoma) or solidtumors (e.g., colorectal cancer, breast cancer (e.g., breast carcinoma),esophageal cancer (e.g., esophageal adenocarcinoma), brain cancer (e.g.,glioblastoma), and kidney cancer (e.g., renal cell carcinoma)),immunoproliferative disorders (e.g., monoclonal IgAhypergammaglobulinemia), vasculitis (e.g., kidney vasculitis,Henoch-Schonlein purpura (IgA associated vasculitis), andpost-streptococcal glomerulonephritis), autoimmune disorders (e.g.,rheumatoid arthritis, systemic lupus erythematosus, linear IgA bullousdisease/linear immunoglobulin A (IgA) dermatosis, and IgA-mediatedepidermolysis bullosa acquisita), IgA pemphigus, celiac disease, andalcoholic cirrhosis. In an embodiment, the disorder is associated withaberrant expression of IgA. In an embodiment, the antibody molecule isused to treat a subject having a disorder described herein, or is atrisk of developing a disorder described herein.

The antibody molecules described herein are typically administered at afrequency that keeps a therapeutically effective level of antibodymolecules in the patient's system until the patient recovers. Forexample, the antibody molecules may be administered at a frequency thatachieves a serum concentration sufficient for at least about 1, 2, 5,10, 20, 30, or 40 antibody molecules to bind each APRIL molecule. In anembodiment, the antibody molecules are administered every 1, 2, 3, 4, 5,6, or 7 days, every 1, 2, 3, 4, 5, or 6 weeks, or every 1, 2, 3, 4, 5,or 6 months.

Methods of administering various antibody molecules are known in the artand are described below. Suitable dosages of the antibody molecules usedwill depend on the age and weight of the subject and the particular drugused.

In an embodiment, the antibody molecule is administered to the subject(e.g., a human subject) intravenously. In an embodiment, the antibodymolecule is administered to the subject at a dose between 0.1 mg/kg and50 mg/kg, e.g., between 0.2 mg/kg and 25 mg/kg, between 0.5 mg/kg and 10mg/kg, between 0.5 mg/kg and 5 mg/kg, between 0.5 mg/kg and 3 mg/kg,between 0.5 mg/kg and 2.5 mg/kg, between 0.5 mg/kg and 2 mg/kg, between0.5 mg/kg and 1.5 mg/kg, between 0.5 mg/kg and 1 mg/kg, between 1 mg/kgand 1.5 mg/kg, between 1 mg/kg and 2 mg/kg, between 1 mg/kg and 2.5mg/kg, between 1 mg/kg and 3 mg/kg, between 1 mg/kg and 2.5 mg/kg, orbetween 1 mg/kg and 5 mg/kg. In an embodiment, the antibody molecule isadministered to the subject at a fixed dose between 10 mg and 1000 mg,e.g., between 10 mg and 500 mg, between 10 mg and 250 mg, between 10 mgand 150 mg, between 10 mg and 100 mg, between 10 mg and 50 mg, between250 mg and 500 mg, between 150 mg and 500 mg, between 100 mg and 500 mg,between 50 mg and 500 mg, between 25 mg and 250 mg, between 50 mg and150 mg, between 50 mg and 100 mg, between 100 mg and 150 mg. between 100mg and 200 mg, or between 150 mg and 250 mg. In an embodiment, theantibody molecule is administered once a week, twice a week, once everytwo weeks, once every three weeks, once every four weeks, once everyeight weeks, once a month, once every two months, or once every threemonths. In an embodiment, the antibody molecule is administered between0.5 mg/kg and 3 mg/kg or between 50 mg and 150 mg, once a week, twice aweek, once every two weeks, or once every four weeks.

The antibody molecules can be used by themselves or conjugated to asecond agent, e.g., a bacterial agent, toxin, or protein, e.g., a secondanti-APRIL antibody molecule. This method includes: administering theantibody molecule, alone or conjugated to a second agent, to a subjectrequiring such treatment. The antibody molecules can be used to delivera variety of therapeutic agents, e.g., a toxin, or mixtures thereof.

IgA Nephropathy

IgA nephropathy (also known as Berger's disease, Berger disease,Berger's syndrome, Berger syndrome, IgA nephritis, IgAN, orsynpharyngitic glomerulonephritis) is the most prevalent, chronicglomerular disease worldwide. Conservative epidemiological estimatescite a global incidence of approximately 5-50 cases/million (children)and 10-40 cases/million (adults). This incidence of disease presents aregional bias with a higher prevalence in Asia and the Americas, with aparticularly higher disease burden in Japan and regions of China. Biopsyconfirmed cases of IgA nephropathy in Japan are projected atapproximately 350,000. In the US, this projection is approximately100,000—as such, it is the most frequently diagnosed 1° glomerulardisease in adults. While a relatively indolent disease, IgA nephropathyleads to end stage renal disease (ESRD), i.e., renal failure in 20-50%of patients within a 20-30 year span. These numbers are likely grosslyunderreported given the need to confirm the disease by kidney biopsy, aprotocol that is variably practiced in various clinical settings. Thedisease has a complex pathogenesis with genetic, epidemiological, andpotentially environmental components to disease etiology, pathology, andprogression. It likewise has a variable clinical presentation rangingfrom asymptomatic to end-stage renal failure (ESRD). There are currentlyno disease-specific treatments to address primary disease orprogression.

The etiology of this disease, as its name implies, has been established.In brief, the disease is caused by the deposition of IgA, typically inthe form of immune complexes in the mesangium of the kidney. A molecularcharacterization of these particular immunoglobulins has been carriedout. These IgAs are of the A1 subclass (IgA1 vs. IgA2), predominantlypolymeric (with J chain-mediated linkages), and apparentlydifferentially o-glycosylated in the hinge region that is interveningbetween CH1 and CH2 domains. In particular, these o-glycans areheterogeneously lacking β1,3 galactose linkages and, as such, arecommonly referred to as galactose-deficient IgA1 (or gdIgA1). As thepathogenesis of this disease can involve a polygenic, multi-hitmechanism for inducing renal pathology and aberrant physiology, IgA1 maybe viewed as the so-called auto-antigen representing this first critical“hit” in a multi-hit model for IgA nephropathy. A set of autoantibodiesfor this disease has likewise been defined and it relates toimmunoglobulins (predominantly IgG) that specifically recognize thisdifferentially glycosylated epitope and promote the formation of immunecomplexes (representing so-called “hit 2”). It should also be noted thatIgA itself is subject to aggregation due to misfolding, conformationalchanges, and potential changes in the N-glycosylation state of theCH2/CH3 glycans.

Without wishing to be bound by theory, it is believed that in anembodiment, aberrantly glycosylated IgA1 levels correlate with diseaseand clinical outcomes in IgA nephropathy. Aberrantly glycosylated IgA1has been characterized directly from kidney biopsies and increasedproduction of aberrantly glycosylated IgA1 was observed in B cells(tonsillar, PBMC) in IgA nephropathy patients. The level ofgalactose-deficient IgA1 in the sera of patients with IgA nephropathy isassociated with disease progression (Zhao et al. Kidney Int. 2012;82(7):790-6). Differential lectin staining demonstrated elevated levelsof aberrantly glycosylated IgA1 in serum and glomeruli of IgAnephropathy patients relative to healthy controls (Allen et al. KidneyInt. 2001; 60(3):969-73).

Based on this evolving disease model, IgA nephropathy may beappropriately viewed as an autoimmune disease with strong and criticalextra-renal involvement. The identification and validation of selectimmune-based targets proposed to play a critical role in diseasepathogenesis, namely the production of IgA and subsequent production ofautoreactive antibodies to this target, represent a logical therapeuticstrategy for treatment. APRIL (TNFSF13) represents particular area offocus for this reason. Additional rationale for targeting APRIL includeemerging genetic data based on multiple, comprehensive genome wideassociation (GWAS) studies along with IgA related genetic disorderse.g., IgA hypogammaglobulinemia related common variable immunoglobulindeficiency (CVID) whose locus maps to defects in TNFRSF13B (TACI) withdirect implications of the role of APRIL-TACI interactions in regulatingIgA synthesis.

IgA nephropathy often does not cause symptoms in the early stages. Thedisease can go unnoticed for years and is sometimes first diagnosed whenroutine tests reveal protein and red blood cells in urine that cannot beseen without a microscope (microscopic hematuria). Signs and symptoms ofIgA nephropathy when kidney function is impaired include, e.g., cola- ortea-colored urine (caused by red blood cells in the urine); repeatedepisodes of cola- or tea-colored urine, sometimes even visible blood inthe urine, usually during or after an upper respiratory or other type ofinfection; pain in the side(s) of the back below the ribs (flank); foamin the toilet water from protein in the urine; swelling (edema) in thehands and feet; and high blood pressure. In an embodiment, the sign orsymptom includes, e.g., one or more of hematuria, proteinuria,albuminuria, hypertension, or an early stage kidney disease (e.g.,requiring dialysis or transplantation). In an embodiment, the sign orsymptom is associated with, e.g., one or more of aberrantly glycosylatedIgA1, auto-antibody formation, deposition of nephritogenic immunecomplexes in the kidney, or inflammation and loss of kidney function.

The classic presentation (in about 40-50% of the cases, more common inyounger adults) of IgA nephropathy is episodic hematuria which usuallystarts within a day or two of a non-specific upper respiratory tractinfection (hence synpharyngitic). Less commonly gastrointestinal orurinary infection can be the inciting agent. All of these infectionshave in common the activation of mucosal defenses and hence IgA antibodyproduction. These episodes can occur on an irregular basis every fewmonths and in most patients eventually subsides. Renal function usuallyremains normal, though rarely, acute kidney failure may occur.

A smaller proportion (in about 20-30% of the cases, usually the olderpopulation) of IgA nephropathy patients have microscopic hematuria andproteinuria (less than 2 gram/day). These patients may not have anysymptoms and are only clinically found if a doctor decides to take aurine sample. Hence, the disease is more commonly diagnosed insituations where screening of urine is compulsory, e.g., school childrenin Japan.

Some (about 5% each) IgA nephropathy patients have the following diseasepresentation: nephrotic syndrome (e.g., 3-3.5 grams of protein loss inthe urine, associated with a poorer prognosis); acute kidney failure(e.g., either as a complication of the frank hematuria, when it usuallyrecovers, or due to rapidly progressive glomerulonephritis which oftenleads to chronic kidney failure); chronic kidney failure (e.g., noprevious symptoms, presents with anemia, hypertension and other symptomsof kidney failure, in people who probably had longstanding undetectedmicroscopic hematuria and/or proteinuria).

A variety of systemic diseases can be associated with IgA nephropathysuch as liver failure, celiac disease, rheumatoid arthritis, reactivearthritis, ankylosing spondylitis and HIV. Diagnosis of IgA nephropathyand a search for any associated disease occasionally reveals such anunderlying serious systemic disease. Occasionally, there aresimultaneous symptoms of Henoch-Schönlein purpura. Some HLA alleles havebeen suspected along with complement phenotypes as being geneticfactors.

IgA nephropathy can be diagnosed by various tests, e.g., urine test,blood tests (e.g., to show increased blood levels of the waste productcreatinine), iothalamate clearance test, kidney imaging (e.g.,ultrasound, X-rays, or cystoscopy), kidney biopsy, or a combinationthereof.

For an adult patient with isolated hematuria, tests such as ultrasoundof the kidney and cystoscopy are usually done first to pinpoint thesource of the bleeding. These tests would rule out kidney stones andbladder cancer, two other common urological causes of hematuria. Inchildren and younger adults, the history and association withrespiratory infection can raise the suspicion of IgA nephropathy. Akidney biopsy is often necessary to confirm the diagnosis. The biopsyspecimen shows proliferation of the mesangium, with IgA deposits onimmunofluorescence and electron microscopy. However, patients withisolated microscopic hematuria (i.e., without associated proteinuria andwith normal kidney function) are not usually biopsied since this isassociated with an excellent prognosis. A urinalysis will show red bloodcells, usually as red cell urinary casts. Proteinuria, usually less than2 grams per day, also may be present. Other renal causes of isolatedhematuria include, e.g., thin basement membrane disease and Alportsyndrome, the latter being a hereditary disease associated with hearingimpairment and eye problems. Other blood tests done to aid in thediagnosis include CRP or ESR, complement levels, ANA, and LDH. Proteinelectrophoresis and immunoglobulin levels can show increased IgA in 50%of all patients.

Treatment with a number of medications can slow the progress of thedisease and help manage symptoms such as high blood pressure, protein inthe urine (proteinuria), and swelling (edema) in the hands and feet.Exemplary therapies for IgA nephropathy include, e.g., high bloodpressure medications (e.g., angiotensin-converting enzyme (ACE)inhibitors or angiotensin receptor blockers (ARBs)), omega-3 fattyacids, immunosuppressants (e.g., corticosteroid medications, such asprednisone), statin therapy, mycophenolate mofetil, ciclosporin,mizoribine, cyclophosphamide (e.g., in combination withanti-platelet/anticoagulants, or in combination with steroids andazathioprine), kidney dialysis, or kidney transplantation. Exemplarytherapies for IgA nephropathy are also described in Floege and Eitner J.Am. Soc. Nephrol. 22: 1785-1794, 2011. Other exemplary therapies for IgAnephropathy are described in the section of “Combination Therapies”herein.

Without wishing to be bound by theory, it is believed that in anembodiment, targeting APRIL selectively reduces IgA. APRIL−/− mice havenormal T and B lymphocyte development, normal T and B cell proliferationin vitro, but decreased serum IgA levels (Castigli et al. Proc Natl AcadSci U S A. 2004; 101(11):3903-8). Discovery of new risk loci for IgAnephropathy implicates genes involved in immunity against intestinalpathogens (Kiryluk et al. Nat Genet. 2014; 46(11):1187-96). Serum levelsand B cell production of APRIL are elevated in patients with IgAnephropathy and correlate with aberrantly glycosylated IgA levels (Zhaiet al. Medicine (Baltimore). 2016; 95(11):e3099). Plasma levels of APRIL(TNFSF13) correlate with progression of chronic kidney disease in IgAnephropathy (Han et al. J Am Soc Nephrol. 2016; 27(2):439-53). Treatmentwith anti-APRIL antibody results in reduction of serum IgA, clearing ofkidney mesangium, and reduction of inflammatory cell infiltration andglomerular injury, in mice (Kim et al. PLoS One. 2015; 10(9):e0137044).Anti-APRIL antibody preserves immune cell homeostasis in bone marrow andspleen (Kim et al. PLoS One. 2015; 10(9):e0137044).

APRIL (TNFSF13) represents a logical biological and therapeutic targetfor the treatment of IgA nephropathy. Without wishing to be bound bytheory, it is believed that in an embodiment, the efficacy of theantibody molecules described herein with respect to the targetedmodulation of APRIL-mediated immunobiolgocial mechanisms is directlyrelevant to treatment of IgA nephropathy. The anti-APRIL antibodymolecules described herein (e.g., humanized anti-APRIL antibodymolecules), e.g., with high biological potency and/or low complementactivation, can be used to treat IgA nephropathy. In an embodiment, theantibody molecule has picomolar APRIL binding affinity and sub-nanomolarreceptor blocking activity to both TACI and BCMA, e.g., in vitro. Inanother embodiment, the antibody molecule functionally interfere withAPRIL mediated downstream cellular signaling, e.g., through thecanonical NFκB activation pathway. In an embodiment, the antibodymolecule is engineered, e.g., as an IgG2 subtype, for purposes ofclinically mitigating against antibody-dependent exacerbation ofcomplement recruitment, e.g., in the kidneys of IgA nephropathypatients. In an embodiment, an antibody molecule described herein canhave an improved safety profile in comparison to more depletive Bcell-based therapeutic approaches, e.g., due to a lesser perturbation ofB and T cell homeostasis as shown in a murine model (Kim et al. PLoSOne. 2015; 10(9):e0137044).

The antibody molecules described herein can be used to treat or preventdifferent stages of IgA nephropathy. In an embodiment, the antibodymolecule is used to treat a symptom associated with IgA nephropathy,e.g., hematuria, proteinuria, albuminuria, hypertension, an early stagekidney disease (e.g., requiring dialysis or transplantation), or acombination thereof. In an embodiment, the antibody molecule reducesaberrantly glycosylated IgA1, auto-antibody formation, deposition ofnephritogenic immune complexes in the kidney, inflammation and loss ofkidney function, or a combination thereof. In an embodiment, the subjectis at low risk, e.g., having minor urinary abnormalities (e.g.,micro-hematuria), normal glomerular filtration rate (GFR), and/or nohypertension. In another embodiment, the subject is at moderate to highrisk, e.g., having proteinuria greater than 0.5-1 g/d and/or GFR reduced(e.g., below 30-50 ml/min) and/or hypertension. In yet anotherembodiment, the subject has acute or rapid GFR loss, e.g., havingnephrotic syndrome or rapidly progressive glomerulonephritis (RPGN), oracute kidney injury (AKI) due to macro-hematuria or other common cause.In an embodiment, the subject has proteinuria greater than 0.5 g/day,e.g., between 0.5-1 g/day or greater than 1 g/day. In an embodiment, thesubject treated for IgA nephropathy has glomerular filtration rate (GFR)less than 50 ml/min, e.g., less than 30 ml/min. In an embodiment, theantibody molecule does not significantly change (e.g., capable ofpreserving) immune cell homeostasis. In another embodiment, the antibodymolecule results in a reduction of IgA not total ablation of IgA.

Diabetic Nephropathy

The antibody molecule described herein can be used to treat or preventdiabetic nephropathy. Diabetic nephropathy (or known as diabetic kidneydisease) is a progressive kidney disease caused, e.g., by damage to thecapillaries in the kidneys' glomeruli. It is typically characterized bynephrotic syndrome and diffuse scarring of the glomeruli. It is oftendue to longstanding diabetes mellitus, and is a prime reason fordialysis. It is classified as a small blood vessel complication ofdiabetes.

Exemplary symptoms of diabetic nephropathy include, but are not limitedto, severe tiredness, headaches, a general feeling of illness, nausea,vomiting, frequent voiding, lack of appetite, itchy skin, or legswelling. The cause of diabetic nephropathy can include, e.g., highblood sugar, advanced glycation end product formation. Cytokines may beinvolved in the development of diabetic nephropathy.

Diabetes can cause a number of changes to the body's metabolism andblood circulation, which likely combine to produce excess reactiveoxygen species. These changes damage the kidney's glomeruli, which leadsto the hallmark feature of albuminuria (Cao and Cooper J DiabetesInvestig. 2011; 2(4): 243-247). As diabetic nephropathy progresses, theglomerular filtration barrier (GFB), which is composed of thefenestrated endothelium, glomerular basement membrane, and epithelialpodocytes, is increasingly damaged (Mora-Fernández et al. J. Physiol.(Lond.) 2014; 592 (Pt 18): 3997-4012). Damage to the glomerular basementmembrane allows proteins in the blood to leak through, leading toaccumulation in Bowman's space as distinct periodic-acid schiff positivenodules (Kimmelstiel-Wilson nodules).

Diagnosis of diabetic nephropathy can be based on the measurement ofhigh levels of albumin in the urine or evidence of reduced kidneyfunction (Lewis and Maxwell Practitioner. 2014; 258(1768):13-7, 2).Albumin measurements can be defined as follows: normal albuminuria:urinary albumin excretion <30 mg/24 h; microalbuminuria: urinary albuminexcretion in the range of 30-299 mg/24 h; clinical (overt) albuminuria:urinary albumin excretion ≥300 mg/24 h. To test kidney function, theperson's estimated glomerular filtration rate (eGFR) is measured from ablood sample. Normal eGFR ranges from 90 to 120 ml/min/1.73 m².

Other treatments that can be used in combination with the antibodymolecule described herein to treat diabetic nephropathy include, e.g.,an angiotensin-converting enzyme (ACE) inhibitor (e.g., captopril,enalapril, lisinopril, or ramipril), an angiotensin II receptor blocker(ARB) (e.g., candesartan cilexetil, irbesartan, losartan, ortelmisartan), a calcium channel blocker (e.g., amlodipine, diltiazem, orverapamil), a diuretic (e.g., chlorthalidone, hydrochlorothiazide, orspironolactone), a beta-blocker (e.g., atenolol, carvedilol, ormetoprolol), and diabetes management (e.g., control of high bloodpressure or blood sugar levels, or reduction of dietary salt intake).

Cancer

The antibody molecule described herein can be used to treat or prevent acancer. Exemplary cancers that can be treated or prevented by theantibody molecules described herein include, but are not limited to,acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),adrenocortical carcinoma, Kaposi sarcoma, an AIDS-related lymphoma,primary central nervous system (CNS) lymphoma, anal cancer, appendixcancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cellcarcinoma, bile duct cancer, bladder cancer, bone cancer (e.g., Ewingsarcoma or osteosarcoma and malignant fibrous histiocytoma), brain tumor(e.g., astrocytomas, brain stem glioma, central nervous system atypicalteratoid/rhabdoid tumor, central nervous system embryonal tumor, centralnervous system germ cell tumor, craniopharyngioma, or ependymoma),breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor (e.g.,gastrointestinal carcinoid tumor), cardiac (heart) tumor, embryonaltumor, germ cell tumor, lymphoma, cervical cancer, cholangiocarcinoma,chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenousleukemia (CML), chronic myeloproliferative neoplasm, colon cancer,colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductalcarcinoma in situ (DCIS), endometrial cancer, ependymoma, esophagealcancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ celltumor, extragonadal germ cell tumor, eye cancer (e.g., intraocularmelanoma or retinoblastoma), fallopian tube cancer, fibrous histiocytomaof bone, osteosarcoma, gallbladder cancer, gastric (stomach) cancer,gastrointestinal carcinoid tumor, gastrointestinal stromal tumors(GIST), germ cell tumor (e.g., central nervous system tumor,extracranial tumor, extragonadal tumor, ovarian cancer, or testicularcancer), gestational trophoblastic disease, glioma, hairy cell leukemia,head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma,hypopharyngeal cancer, intraocular melanoma, islet cell tumor,pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer (e.g.,renal cell cancer or Wilms tumor), Langerhans cell histiocytosis (LCH),laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia (ALL),acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), or hairy cell leukemia), lip andoral cavity cancer, liver cancer, lung cancer (e.g., non-small cell lungcancer (NSCLC) or small cell lung cancer), lymphoma (e.g., aids-related,Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, or primary central nervous system (CNS) lymphoma),Waldenström macroglobulinemia, male breast cancer, malignant fibroushistiocytoma of bone and osteosarcoma, melanoma (e.g., intraocular (eye)melanoma), Merkel cell carcinoma, mesothelioma, metastatic squamous neckcancer, midline tract carcinoma, mouth cancer, multiple endocrineneoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferativeneoplasm, chronic myeloproliferative neoplasm, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oralcancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcomaand malignant fibrous histiocytoma of bone, ovarian cancer (e.g.,epithelial ovarian cancer or germ cell ovarian tumor), pancreaticcancer, pancreatic neuroendocrine tumors (islet cell tumors),papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma,pituitary tumor, pleuropulmonary blastoma, peritoneal cancer, prostatecancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma,rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), Sezarysyndrome, skin cancer (e.g., melanoma, Merkel cell carcinoma, ornonmelanoma skin cancer), small intestine cancer, squamous cellcarcinoma, testicular cancer, throat cancer, thymoma and thymiccarcinoma, thyroid cancer, transitional cell cancer of the renal pelvisand ureter, urethral cancer, endometrial uterine cancer, vaginal cancer,vulvar cancer, or a metastatic lesion thereof.

In an embodiment, the cancer is a hematological cancer, e.g., a lymphomaor leukemia, e.g., chosen from B-cell non-Hodgkin's lymphoma, chroniclymphocytic leukemia (CLL), Hodgkin's lymphoma, multiple myeloma,Waldenström macroglobulinemia, or lymphoplasmacytic lymphoma. In anembodiment, the cancer is a multiple myeloma. In another embodiment, thecancer is a solid tumor, e.g., chosen from colorectal cancer, breastcancer (e.g., breast carcinoma), esophageal cancer (e.g., esophagealadenocarcinoma), brain cancer (e.g., glioblastoma), or kidney cancer(e.g., renal cell carcinoma).

In an embodiment, the antibody molecule is used to treat a lymphoma.Other treatments that can be used in combination with the antibodymolecule described herein to treat lymphoma include, e.g., chemotherapy,immunotherapy, targeted drug therapy, radiation therapy, and stem celltransplant. Exemplary targeted drug therapy includes a CD20 inhibitor(e.g., rituximab (RITUXAN® or ibritumornab tiuxetan (ZEVALIN®)).

In an embodiment, the antibody molecule is used to treat a leukemia.Other treatments that can be used in combination with the antibodymolecule described herein to treat leukemia include, e.g., chemotherapy,immunotherapy, targeted drug therapy, radiation therapy, and stem celltransplant. Exemplary targeted drug therapy includes a tyrosine kinaseinhibitor (e.g., imatinib (GLEEVEC®). In an embodiment, the antibodymolecule is used to treat a multiple myeloma. Other treatments that canbe used in combination with the antibody molecule described herein totreat multiple myeloma include, e.g., chemotherapy, corticosteroids,immunotherapy, targeted drug therapy, radiation therapy, and stem celltransplant. Exemplary targeted drug therapy includes, e.g., athalidomide analog (e.g., thalidomide (THALOMID®), lenalidomide(REVLIMID®), or pomalidomide (POMALYST®)).

In an embodiment, the antibody molecule is used to treat Waldenströmmacroglobulinemia. Other treatments that can be used in combination withthe antibody molecule described herein to treat Waldenströmmacroglobulinemia include, e.g., plasma exchange, chemotherapy,immunotherapy, targeted drug therapy, and stem cell transplant.

In an embodiment, the antibody molecule is used to treat a colorectalcancer. Other treatments that can be used in combination with theantibody molecule described herein to treat colorectal cancer include,e.g., surgery, chemotherapy, radiation therapy, immunotherapy, andtargeted drug therapy. Exemplary targeted drug therapy includes, e.g., aVEGF inhibitor (e.g., bevacizumab (AVASTIN®)), an EGFR inhibitor (e.g.,cetuximab (ERBITUX®), panitumumab (VECTIBIX®)), and dual VEGFR2-TIE2tyrosine kinase inhibitor (e.g., regorafenib (STIVARGA®)).

In an embodiment, the antibody molecule is used to treat a breastcancer, e.g., a breast carcinoma. Other treatments that can be used incombination with the antibody molecule described herein to treat breastcancer include, e.g., surgery, chemotherapy, radiation therapy, hormonetherapy, immunotherapy, and targeted drug therapy. Exemplary target drugtherapy includes, e.g., an HER2 inhibitor (e.g., trastuzumab(HERCEPTIN®), pertuzumab (PERJETA®), ado-trastuzumab (KADCYLA®), orlapatinib (TYKERB®)) or a VEGF inhibitor (e.g., bevacizumab (AVASTIN®)).

In an embodiment, the antibody molecule is used to treat an esophagealcancer, e.g., an esophageal adenocarcinoma. Other treatments that can beused in combination with the antibody molecule described herein to treatesophageal cancer include, e.g., surgery, chemotherapy, radiationtherapy, and immunotherapy.

In an embodiment, the antibody molecule is used to treat a brain cancer,e.g., a glioblastoma. Other treatments that can be used in combinationwith the antibody molecule described herein to treat brain cancerinclude, e.g., surgery, chemotherapy, radiation therapy, radiosurgery,immunotherapy, and targeted drug therapy. Exemplary targeted drugtherapy includes, e.g., a VEGF inhibitor (e.g., bevacizumab (AVASTIN®)).

In an embodiment, the antibody molecule is used to treat a kidneycancer, e.g., a renal cell carcinoma. Other treatments that can be usedin combination with the antibody molecule described herein to treatkidney cancer include, e.g., surgery, cryoablation, radiofrequencyablation, radiation therapy, immunotherapy, and targeted drug therapy.Exemplary targeted drug therapy includes, e.g., a VEGF inhibitor (e.g.,bevacizumab (AVASTIN®)), a tyrosine kinase inhibitor (e.g., axitinib(INLYTA®), pazopanib (VOTRIENT®), sorafenib (NEXAVAR®), or sunitinib(SUTENT®), or an mTOR inhibitor (e.g., temsirolimus (TORISEL®) oreverolimus (AFINITOR®).

Immunoproliferative Disorders

The antibody molecule described herein can be used to treat or preventan immunoproliferative disorder Immunoproliferative disorders (alsoknown as immunoproliferative diseases or immunoproliferative neoplasms)are disorders of the immune system that are characterized by theabnormal proliferation of the primary cells of the immune system (e.g.,B cells, T cells and Natural killer (NK) cells) or by the excessiveproduction of immunoglobulins (e.g., antibodies).

Exemplary immunoproliferative disorders include, but are not limited to,lymphoproliferative disorders (LPDs), hypergammaglobulinemia, andparaproteinemia. Lymphoproliferative disorders include severalconditions in which lymphocytes are produced in excessive quantities.They typically occur in patients who have compromised immune systems.Hypergammaglobulinemia is often characterized by increased levels ofimmunoglobulins in the blood serum. Paraproteinemia or monoclonalgammopathy is the presence of excessive amounts of a single monoclonalgammaglobulin (e.g., a paraprotein) in the blood. In an embodiment, theantibody molecule is used to treat monoclonal IgAhypergammaglobulinemia.

Vasculitis

The antibody molecule described herein can be used to treat or preventvasculitis. Vasculitis is a group of disorders that destroy bloodvessels by inflammation. Vasculitis is primarily caused by leukocytemigration and resultant damage. Exemplary types of vasculitis include,but are not limited to, microscopic polyarteritis (poly-angiitis),Wegener's granulomatosis, Henoch Schonlein purpura and polyarteritisnodosa.

In an embodiment, the antibody molecule is used to treatHenoch-Schonlein purpura (IgA associated vasculitis).

Henoch-Schönlein purpura (HSP, also known as anaphylactoid purpura,purpura rheumatica, or Schönlein-Henoch purpura) is a disease of theskin and other organs that most commonly affects children. HSP is asystemic vasculitis (inflammation of blood vessels) and is characterizedby deposition of immune complexes of IgA and complement component 3 (C3)on arterioles, capillaries, and venules. In the skin, the disease causespalpable purpura (small hemorrhages); often with joint and abdominalpain. With kidney involvement, there may be a loss of small amounts ofblood and protein in the urine; in a small proportion of cases, thekidney involvement proceeds to chronic kidney disease even irreversiblekidney damage. HSP is often preceded by an infection, such as a throatinfection.

Symptoms of Henoch-Schönlein purpura include, e.g., rash (purpura),swollen or sore joints (arthritis), gastrointestinal symptoms (e.g.,abdominal pain, nausea, vomiting or bloody stools), and kidneyinvolvement (e.g., protein or blood in the urine). Serum levels of IgAare high in HSP patients.

Standards for defining Henoch-Schönlein purpura include, e.g., the 1990American College of Rheumatology (ACR) classification (Mills et al.(1990). Arthritis and Rheumatism 33 (8): 1114-21), the 1994 Chapel HillConsensus Conference (CHCC) (Jennette et al. (1994) Arthritis andRheumatism 37 (2): 187-92), and the 2006 European League AgainstRheumatism (EULAR) and Pediatric Rheumatology Society (PReS)classification, which includes palpable purpura as a mandatorycriterion, together with at least one of the following findings: diffuseabdominal pain, predominant IgA deposition (confirmed on skin biopsy),acute arthritis in any joint, and renal involvement (as evidenced by thepresence of blood and/or protein in the urine) (Ozen et al. (2006)Annals of Rheumatic Diseases 65 (7): 936-41).

Other treatments that can be used in combination with the antibodymolecule described herein to treat Henoch-Schönlein purpura include,e.g., analgesics for the abdominal and joint pains, steroids (e.g., oralsteroids or a combination of intravenous methylprednisolone (steroid),cyclophosphamide and dipyridamole followed by prednisone). Otherregimens also include, e.g., steroids/azathioprine, andsteroids/cyclophosphamide (with or without heparin and warfarin), orintravenous immunoglobulin (IVIG).

In another embodiment, the antibody molecule is used to treat acuteproliferative glomerulonephritis, e.g., post-streptococcalglomerulonephritis.

Acute proliferative glomerulonephritis is a disorder of the glomeruli(glomerulonephritis), or small blood vessels in the kidneys. It is acommon complication of bacterial infections, typically skin infection byStreptococcus bacteria types 12, 4 and 1 (impetigo) but also afterstreptococcal pharyngitis, for which it is also known as postinfectiousor poststreptococcal glomerulonephritis. The infection causes bloodvessels in the kidneys to develop inflammation, which hampers the renalorgans ability to filter urine.

The pathophysiology of this disorder is consistent with an immunecomplex mediated mechanism. This disorder produces proteins that havedifferent antigenic determinants, which in turn have an affinity forsites in the glomerulus. As soon as binding occurs to the glomerulus,via interaction with properdin, complement is activated. Complementfixation causes the generation of additional inflammatory mediators.

Symptoms of acute proliferative glomerulonephritis include, e.g.,hematuria, oliguria, edema, hypertension, fever, headache, malaise,anorexia, and nausea.

Other treatments that can be used in combination with the antibodymolecule described herein to treat cute proliferative glomerulonephritisincludes, e.g., blood pressure (BP) control and control of the amount ofpotassium in individuals with oliguric acute kidney injury.

Autoimmune Disorders

The antibody molecule described herein can be used to treat or preventan autoimmune disorder. Exemplary autoimmune disorders that can betreated or prevented by the antibody molecule described herein include,but are not limited to, acute Disseminated Encephalomyelitis (ADEM),acute necrotizing hemorrhagic leukoencephalitis, Addison's disease,agammaglobulinemia, alopecia areata, amyloidosis, ankylosingspondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome(APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmunedysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia,autoimmune immunodeficiency, autoimmune inner ear disease (AIED),autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis,autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP),autoimmune thyroid disease, autoimmune urticaria, axonal & neuronalneuropathies, Balo disease, Behcet's disease, bullous pemphigoid,cardiomyopathy, Castleman disease, celiac disease, Chagas disease,chronic fatigue syndrome, chronic inflammatory demyelinatingpolyneuropathy (CIDP), chronic recurrent multifocal ostomyelitis (CRMO),Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosalpemphigoid, Crohn's disease, Cogans syndrome, cold agglutinin disease,congenital heart block, coxsackie myocarditis, CREST disease, essentialmixed cryoglobulinemia, demyelinating neuropathies, dermatitisherpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica),discoid lupus, Dressler's syndrome, endometriosis, eosinophilicesophagitis, eosinophilic fasciitis, Erythema nodosum, experimentalallergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosingalveolitis, giant cell arteritis (temporal arteritis), giant cellmyocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosiswith polyangiitis (GPA) (formerly called Wegener's Granulomatosis),Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis,Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura,Herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenicpurpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,immunoregulatory lipoproteins, inclusion body myositis, interstitialcystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes),juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneousconjunctivitis, linear IgA disease (LAD), pupus (SLE), Lyme disease,chronic, Meniere's disease, microscopic polyangiitis, mixed connectivetissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiplesclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica(Devic's), neutropenia, ocular cicatricial pemphigoid, optic neuritis,palindromic rheumatism, PANDAS (Pediatric Autoimmune NeuropsychiatricDisorders Associated with Streptococcus), paraneoplastic cerebellardegeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Rombergsyndrome, Parsonnage-Turner syndrome, Pars planitis (peripheraluveitis), pemphigus, peripheral neuropathy, perivenousencephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritisnodosa, Type I, II, & III autoimmune polyglandular syndromes,polymyalgia rheumatica, polymyositis, postmyocardial infarctionsyndrome, postpericardiotomy syndrome, progesterone dermatitis, primarybiliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriaticarthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure redcell aplasia, raynauds phenomenon, reactive arthritis, reflexsympathetic dystrophy, reiter's syndrome, relapsing polychondritis,restless legs syndrome, retroperitoneal fibrosis, rheumatic fever,rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiffperson syndrome, subacute bacterial endocarditis (SBE), Susac'ssyndrome, sympathetic ophthalmia, Takayasu's arteritis, temporalarteritis/Giant cell arteritis, thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, transverse myelitis, Type 1 diabetes, ulcerativecolitis, undifferentiated connective tissue disease (UCTD), uveitis,vasculitis, vesiculobullous dermatosis, vitiligo, Wegener'sgranulomatosis (also known as Granulomatosis with Polyangiitis (GPA).

In an embodiment, the autoimmune disorder is rheumatoid arthritis,systemic lupus erythematosus, a linear IgA bullous disease (e.g., linearimmunoglobulin A (IgA) dermatosis), or IgA-mediated epidermolysisbullosa acquisita.

In an embodiment, the antibody molecule is used to treat rheumatoidarthritis. Other treatments that can be used in combination with theantibody molecule described herein to treat rheumatoid arthritisincludes, e.g., an NSAID, a steroid (e.g., corticosteroid), adisease-modifying antirheumatic drug (DMARD) (e.g., methotrexate(TREXALL®), leflunomide (ARAVA®), hydroxychloroquine (PLAQUENIL®), orsulfasalazine (AZULFIDINE®), a biologic response modifier (e.g.,abatacept (ORENCIA®), adalimumab (HUMIRA®), anakinra (KINERET®),certolizumab (CIMZIA®), etanercept (ENBREL®), golimumab (SIMPONI®),infliximab (REMICADE®), rituximab (RITUXAN®) and tocilizumab (ACTEMRA®),or Tofacitinib (XELJANZ®)), or surgery.

In an embodiment, the antibody molecule is used to treat systemic lupuserythematosus. Other treatments that can be used in combination with theantibody molecule described herein to treat rheumatoid arthritisincludes, e.g., an NSAID, an antimalarial drug (e.g., hydroxychloroquine(PLAQUENIL®), corticosteroid (e.g., prednisone), an immunosuppressant(e.g., azathioprine (IMURAN®, AZASAN®), mycophenolate (CELLCEPT®),leflunomide (ARAVA®), or methotrexate (TREXALL®)), or a BAFF inhibitor(e.g., belimumab (BENLYSTA®).

In an embodiment, the antibody molecule is used to treat a linear IgAbullous disease (e.g., linear immunoglobulin A (IgA) dermatosis). Othertreatments that can be used in combination with the antibody moleculedescribed herein to treat a linear IgA bullous disease (e.g., linearimmunoglobulin A (IgA) dermatosis) include, e.g., corticosteroids (e.g.,prednisone or prednisolone), an antibiotic (e.g., tetracycline,erythromycin, sulfapyridine), colchicine, or mycophenolate mofetil.

In an embodiment, the antibody molecule is used to treat IgA-mediatedepidermolysis bullosa acquisita. Other treatments that can be used incombination with the antibody molecule described herein to treatIgA-mediated epidermolysis bullosa acquisita includes, e.g., anantibiotic, an anti-inflammatory drug (e.g., corticosteroid), orsurgery.

Other Disorders

The antibody molecule described herein can be used to treat or preventother disorders, e.g., IgA pemphigus, celiac disease, or alcoholiccirrhosis.

In an embodiment, the antibody molecule is used to treat or prevent IgApemphigus. Other treatments that can be used in combination with theantibody molecule described herein to treat IgA pemphigus include, e.g.,corticosteroid, an immunosuppressant (e.g., azathioprine (IMURAN®),methotrexate (TREXALL®), or mycophenolate mofetil (CELLCEPT®)), an CD-20inhibitor (e.g., rituximab (RITUXAN®), an antibiotic, an antiviralagent, or an antifungal agent.

In an embodiment, the antibody molecule is used to treat or preventceliac disease. Other treatments that can be used in combination withthe antibody molecule described herein to treat celiac disease include,e.g., a gluten-free diet, a vitamin or mineral supplement, or a steroid.

In an embodiment, the antibody molecule is used to treat or preventalcoholic cirrhosis. Other treatments that can be used in combinationwith the antibody molecule described herein to treat alcoholic cirrhosisinclude, e.g., an immunosuppressant (e.g., azathioprine, prednisone,azathioprine, cyclosporine, or methotrexate) or liver transplant.

Combination Therapies

The antibody molecules can be used in combination with other therapies.For example, the combination therapy can include an antibody moleculeco-formulated with, and/or co-administered with, one or more additionaltherapeutic agents, e.g., one or more additional therapeutic agentsdescribed herein. In other embodiments, the antibody molecules areadministered in combination with other therapeutic treatment modalities,e.g., other therapeutic treatment modalities described herein. Suchcombination therapies may advantageously utilize lower dosages of theadministered therapeutic agents, thus avoiding possible toxicities orcomplications associated with the various monotherapies.

Administered “in combination”, as used herein, means that two (or more)different treatments are delivered to the subject before, or during thecourse of the subject's affliction with a disorder. In an embodiment,two or more treatments are delivered prophylactically, e.g., before thesubject has the disorder or is diagnosed with the disorder. In anotherembodiment, the two or more treatments are delivered after the subjecthas developed or diagnosed with the disorder. In some embodiments, thedelivery of one treatment is still occurring when the delivery of thesecond begins, so that there is overlap. This is sometimes referred toherein as “simultaneous” or “concurrent delivery.” In other embodiments,the delivery of one treatment ends before the delivery of the othertreatment begins. In some embodiments of either case, the treatment ismore effective because of combined administration. For example, thesecond treatment is more effective, e.g., an equivalent effect is seenwith less of the second treatment, or the second treatment reducessymptoms to a greater extent, than would be seen if the second treatmentwere administered in the absence of the first treatment, or theanalogous situation is seen with the first treatment. In someembodiments, delivery is such that the reduction in a symptom, or otherparameter related to the disorder is greater than what would be observedwith one treatment delivered in the absence of the other. The effect ofthe two treatments can be partially additive, wholly additive, orgreater than additive. The delivery can be such that an effect of thefirst treatment delivered is still detectable when the second isdelivered.

In certain embodiments, the additional agent is a second antibodymolecule, e.g., an antibody molecule different from a first antibodymolecule. Exemplary antibody molecules that can be used in combinationinclude, but are not limited to, any combination of the antibodymolecules listed in Table 1 or 5.

In an embodiment, the antibody molecule is administered in combinationwith a second therapy to treat or prevent IgA nephropathy.

In an embodiment, the antibody molecule is administered in combinationwith an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensinreceptor blocker (ARB).

In an embodiment, the antibody molecule is administered in combinationwith an Fc decoy receptor, e.g., a soluble Fc receptor. In anembodiment, the soluble Fc receptor is a soluble Fc-gamma receptor IIB.In an embodiment, the soluble Fc receptor is SM101/BAX 1810 (Baxalta).In an embodiment, the soluble Fc receptor is administered at a dosebetween 1 mg/kg and 50 mg/kg, e.g., between 5 mg/kg and 15 mg/kg,between 12 mg/kg and 24 mg/kg, or between 20 mg/kg and 30 mg/kg.

In an embodiment, the antibody molecule is administered in combinationwith repository corticotropin (ACTHAR®). Repository corticotropin is anadrenocorticotropic hormone (ACTH) analogue. In an embodiment,repository corticotropin is administered at a dose between 50 U and 150U, e.g., between 80 U and 120 U, by subcutaneous injection, twice orthree times a week. In an embodiment, repository corticotropin isadministered at a dose of 120 U, by subcutaneous injection, e.g., once,twice, or three times a week.

In an embodiment, the antibody molecule is administered in combinationwith mycophenolate mofetil (MMF). Mycophenolate mofetil is the2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressiveagent and inosine monophosphate dehydrogenase (IMPDH) inhibitor. In anembodiment, mycophenolate mofetil is administered at a dose of between0.5 g and 2 g, e.g., between 1 g and 1.5 g or between 1.5 g and 2 g,orally or intravenously, e.g., once, twice, or three times a day.

In an embodiment, the antibody molecule is administered in combinationwith bortezomib (VELCADE®). Bortezomib, also known as[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronicacid, is a proteasome inhibitor. In an embodiment, bortezomib isadministered at a dose at between 0.5 mg/m² and 2.5 mg/m², e.g., between1 mg/m² and 1.5 mg/m², e.g. every three days or every week.

In an embodiment, the antibody molecule is administered in combinationwith allopurinol (ZYLOPRIM®). Allopurinol, also known as1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one, is a purine analog. In anembodiment, allopurinol is administered at a dose between about 50 mgand 1000 mg, e.g., between 100 mg and 600 mg or between 200 and 300 mg,orally, e.g., once a day or once two days.

In an embodiment, the antibody molecule is administered in combinationwith prednisone and/or cyclophosphamide. In an embodiment, prednisone isadministered at a dose between 0.2 mg/kg and 2 mg/kg, e.g., between 0.5mg/kg and 1 mg/kg, e.g., once a day. In an embodiment, cyclophosphamideis administered at a dose between 0.2 g and 2 g, e.g., between 0.5 g and1 g, e.g., once a day.

In an embodiment, the antibody molecule is administered in combinationwith rituximab (RITUXAN®). Rituximab is a chimeric anti-CD20 monoclonalantibody. In an embodiment, rituximab is administered at a dose between100 mg/m² and 500 mg/m², e.g., between 200 mg/m² and 450 mg/m² orbetween 300 mg/m² and 400 mg/m², intravenously, e.g., once weekly, onceevery two weeks, once every four weeks, or once every eight weeks.

In an embodiment, the antibody molecule is administered in combinationwith blisibimod. Blisibimod, also known as A-623 or AMG 623, is aselective antagonist of B-cell activating factor (BAFF, also known asB-lymphocyte stimulator or BLyS).

In an embodiment, the antibody molecule is administered with budesonide.In an embodiment, the budesonide is NEFECON®, an oral formulation thatreleases budesonide.

In an embodiment, the antibody molecule is administered with valsartanand/or probucol. In an embodiment, valsartan is administered at a dosebetween 50 mg/day and 200 mg/day, e.g., between 80 mg/day and 160mg/day. In an embodiment, probucol is administered at a dose between 500mg/day and 1000 mg/day, e.g., between 700 mg/day and 800 mg/day.

In an embodiment, the antibody molecule is administered in combinationwith OPL-CCL2-LPM. OPL-CCL2-LPM is a recombinant fusion proteincomprised of the human CCL2 (monocyte chemoattractant protein-1)chemokine fused to a truncated form of the enzymatically active A1domain of Shigella dysenteriae holotoxin (SA1). In an embodiment,OPL-CCL2-LPM is administered at a dose between 0.001 mg/kg and 1 mg/kg,e.g., between 0.01 mg/kg and 0.5 mg/kg or 0.05 mg/kg and 0.1 mg/kg,e.g., intravenously.

In an embodiment, the antibody molecule is administered in combinationwith methylprednisolone. In an embodiment, methylprednisolone isadministered at a dose between 0.1 mg/kg and 2 mg/kg/day, e.g., between0.2 mg/kg/day and 1.5 mg/kg/day or 0.5 mg/kg/day and 1 mg/kg/day, e.g.,orally.

In an embodiment, the antibody molecule is administered in combinationwith sirolimus. Sirolimus, also known as rapamycin, can inhibit IL-2 andother cytokines receptor-dependent signal transduction mechanisms, viaaction on mTOR, and thereby block activation of T and B cells. In anembodiment, sirolimus is administered at dose between 0.2 mg/day and 2mg/day, e.g., between 0.5 mg/day and 1 mg/day.

In an embodiment, the antibody molecule is administered in combinationwith a renin-angiotensin system (RAS) blocker. For example, the RASblocker can be an angiotensin-converting enzyme (ACE) inhibitor or anAT1 receptor blocker (ARB). Exemplary ACE inhibitors that can be used incombination with the antibody molecule described herein include, e.g.,benazepril (LOTENSIN®), captopril, enalapril (VASOTEC®), fosinopril,lisinopril (ZESTRIL®), moexipril (UNIVASC®), perindopril (ACEON®),quinapril (ACCUPRIL®), ramipril (ALTACE®), or trandolapril (MAVIK®).Exemplary AT1 receptor blockers that can be used in combination with theantibody molecule described herein include, e.g., candesartan(ATACAND®), eprosartan (TEVETEN®), irbesartan (AVAPRO®), losartan(COZAAR®), olmesartan (BENICAR®), telmisartan (MICARDIS®), or valsartan(DIOVAN®).

In an embodiment, the antibody molecule is administered in combinationwith fostamatinib. Fostamatinib is a prodrug of the active compoundtamatinib (R-406), which is an inhibitor of the enzyme spleen tyrosinekinase (Syk). In an embodiment, fostamatinib is administered at a dosebetween about 50 mg and 200 mg, e.g., between 100 mg and 150 mg, e.g.,orally, e.g., every day.

In an embodiment, the antibody molecule is administered in combinationwith paricalcitol. In an embodiment, paricalcitol is administered at adose between about 0.2 mg and 2 mg, e.g., between 0.5 mg and 1 mg, e.g.,every day.

In an embodiment, the antibody molecule is administered in combinationwith ramipril. In an embodiment, ramipril is administered at a dosebetween about 0.5 mg and 5 mg, e.g., between 1 mg and 4 mg or between 2mg and 3 mg, e.g., every day.

In an embodiment, the antibody molecule is administered in combinationwith an angiotensin-converting-enzyme (ACE) inhibitor. In an embodiment,the ACE inhibitor is enalapril (VASOTEC®).

In an embodiment, the antibody molecule is administered in combinationwith an immunosuppressant. In an embodiment, the immunosuppressant istacrolimus. Tacrolimus, also known as FK-506 or fujimycin, is amacrolide calcineurin inhibitor.

In an embodiment, the antibody molecule is administered in combinationwith omega-3 fatty acids.

In an embodiment, the antibody molecule is administered in combinationwith CCX168. CCX168 is an orally administered C5aR inhibitor.

Exemplary therapies that can be used in combination with an antibodymolecule or composition described herein to treat or prevent otherdisorders are also described in the section of “Methods of Treating orPreventing Disorders” herein.

Methods of Diagnosis

In some aspects, the present disclosure provides a diagnostic method fordetecting the presence of APRIL in vitro (e.g., in a biological sample,such as a biopsy or blood sample) or in vivo (e.g., in vivo imaging in asubject). The method includes: (i) contacting the sample with anantibody molecule described herein, or administering to the subject, theantibody molecule; (optionally) (ii) contacting a reference sample,e.g., a control sample (e.g., a control biological sample, such as abiopsy or blood sample) or a control subject with an antibody moleculedescribed herein; and (iii) detecting formation of a complex between theantibody molecule and APRIL in the sample or subject, or the controlsample or subject, wherein a change, e.g., a statistically significantchange, in the formation of the complex in the sample or subjectrelative to the control sample or subject is indicative of the presenceof APRIL in the sample. The antibody molecule can be directly orindirectly labeled with a detectable substance to facilitate detectionof the bound or unbound antibody. Suitable detectable substances includevarious enzymes, prosthetic groups, fluorescent materials, luminescentmaterials and radioactive materials, as described above and described inmore detail below.

The term “sample,” as it refers to samples used for detecting apolypeptide (e.g., APRIL) or a nucleic acid encoding the polypeptideincludes, but is not limited to, cells, cell lysates, proteins ormembrane extracts of cells, body fluids such as blood, or tissue samplessuch as biopsies.

Complex formation between the antibody molecule, and APRIL, can bedetected by measuring or visualizing either the antibody molecule boundto APRIL or unbound antibody molecule. Any suitable detection assays canbe used, and conventional detection assays include an enzyme-linkedimmunosorbent assays (ELISA), a radioimmunoassay (RIA) or tissueimmunohistochemistry. Alternative to labeling the antibody molecule, thepresence of APRIL can be assayed in a sample by a competitionimmunoassay utilizing standards labeled with a detectable substance andan unlabeled antibody molecule. In this assay, the biological sample,the labeled standards and the antibody molecule are combined and theamount of labeled standard bound to the unlabeled binding molecule isdetermined. The amount of APRIL in the sample is inversely proportionalto the amount of labeled standard bound to the antibody molecule.

The antibody molecules described herein can be used to diagnosedisorders that can be treated or prevented by the antibody moleculesdescribed herein. The detection or diagnostic methods described hereincan be used in combination with other methods described herein to treator prevent a disorder described herein.

EXAMPLES Example 1: Immunization and Selection of Anti-APRIL Antibodies

CD-1 IGS (outbred stock) mice (Charles River Laboratories), female(20-25 g weight), 7-8 weeks old were immunized intraperitoneally (i.p.)with 10 μg of recombinant, oligomeric FLAG-ACRP30headless APRIL hereinreferred to as FLAG-ACR-APRIL. For purposes of potentially generating aspecies cross reactive (mouse and human) anti-APRIL antibody response,both autologous and heterologous immunizations were carried out andcomprised the use of human and/or mouse APRIL as immunogens. FLAG-taggedAPRIL immunogens were formulated in a 200 μl volume consisting of 100 μlsterile PBS and 100 μl emulsified RIBI adjuvant system (Sigma Aldrich)comprised of a defined mixture of Monophosphoryl Lipid A (MPL, isolatedfrom Salmonella minnesota) and synthetic trehalose dicorynomycolate(TDM, an analogue of trehalose dimycolate from the cord factor of thetubercle bacillus). 3 mice per arm were immunized twice weekly for up tofour weeks. Serum titers of anti-APRIL antibodies were detectedsubsequently by indirect ELISA using FLAG-GCN4 APRIL, R&D Systems. Inbrief, 50 ng FLAG-GCN4 hAPRIL (105-250) or FLAG-GCN4 mAPRIL (96-241) inPBS were coated on Maxisorp 96-well flat bottom plates (NUNC #439454),overnight at 4° C. Coated plates were blocked in 1× blocking buffercontaining 5% BLOTTO™ in PBS and 0.05% Tween-20 (PBST) for 1 hour atroom temperature. All subsequent incubation steps were followed out withan intervening 3× wash step in PBST. Anti-APRIL antibody titers weredetermined from a fold-dilution of mouse sera (in PBS) initiallystarting at 1:1000 and followed by incubation of a 1:5000 HRP conjugatedrabbit anti-mouse IgG secondary antibody (Jackson ImmunoresearchLaboratories) for 1 hour at room temperature. Anti-APRIL immunoglobulinreactivity was visualized using 100 μl/well of freshly prepared TMBsubstrate (KPL). Colorimetric development was carried out for up to 10minutes at room temperature before quenching enzymatic reaction by theaddition of 100 μl of 1N sulfuric acid and quantification by absorbanceat 450 nm. Mice with strong seropositive titers against primaryimmunogen (human or mouse APRIL) were boosted by tail vein injectionthree days prior to sacrifice, removal of spleen and isolation ofsplenoctye fusions. Mice with preferable species cross-reactivity fromserum profiling were noted.

P3X63Ag8.653 plasmacytomas (ATCC # CRL-1580), herein referred to as P3Xcells were used as source of fusion partner myelomas.Splenically-derived B cell clones were immortalized using publishedmethods with modification. In brief, P3X cells were cultured at least 1week prior to use and maintained in log phase to achieve a target celldensity of between 6×10⁵ and 1.2×10⁶ cells/mL and 95% viability the dayprior to subsequently performing the splenic fusion. Spleen cells wereisolated from 2-3 mice per immunization arm following euthanization andcardiac puncture and collected into DMEM+1% antibiotic(penicillin/streptomycin), followed by gently washing centrifugation(2×) to pellet tissue debris and clarify suspended splenocytes.Splenocytes were then pelleted by centrifugation for 10 min at 400×g at4° C., and red blood cells lysed at room temperature for 5 minutesfollowing gentle resuspension of cell pellet in 1× red blood cell lysisbuffer. Splenocytes were collected by centrifugation (2×) followingdilution with ice cold DMEM. P3X cells were also washed 3X in DMEM priorto fusion.

Mouse splenocytes were fused with P3X cells in fusion medium (50% PEG1450, Sigma Aldrich)) at a 3:1 ratio in accordance with establishedmethods. In brief, pre-warmed PEG was added gradually to pelletedmixture of splenocytes and P3X cells (37° C., with gentle resuspension)followed by gradual addition of pre-warmed DMEM. Fused cells werecollected by low speed centrifugation and resuspended in hybridomaselective media (hypoxanthine-aminopterin-thymidine, Sigma Aldrich)followed by incubation at 37° C. for 30 minutes. Fused cells sere platedin a 96 well plate at a density of approximately 2.0×10⁶ spleen cellsper plate (20,000 cells per well).

Hybridoma supernatants were screened by ELISA on day 14 post-fusion asdescribed (Example 2). In brief, supernatants from conditioned mediawere quantified for total IgG by bioinferometry using AMC anti mouse IgGquantification kit (Pall Biosciences). Supernatants from hybridomaconditioned media were normalized to 10 μg/mL when possible and assayedfor APRIL reactivity to both FLAG-GCN4-hAPRIL and FLAG GCN4-mAPRIL asdescribed. A counter screen using non-APRIL FLAG-tagged protein(FLAG-ACR30-myc-his) was also included to exclude clones with a strongimmunoreactivity to either FLAG or ACRP30 specific epitopes(non-relevant epitopes present in original immunogen). APRIL positivehybridomas (human APRIL or mouse) were screened for receptor blockingactivity by ELISA as described in Example 3. In brief, recombinantTACI-Fc was coated on to Maxisorp 96-well flat bottom plates at 100ng/well in 0.1 M Carbonate-Bicarbonate Buffer (pH 9.6), overnight at 4°C. Plates were blocked with 1% BSA in 1×PBS for 1 hour at 37° C.followed by 3× washing in 1×PBST (with 0.025% Tween). RecombinantFLAG-tagged APRIL (mouse or human) at a concentration of 50 ng/mL waspremixed in binding buffer with supernatant from hybridoma medianormalized when possible to 10 μg/mL IgG concentration. Antibody-APRILpreincubation was carried out for 1 hour at 30° C. with mixing prior toadding to TACI-Fc coated plates, followed by a 1-hour incubation,likewise at 30° C. Detection of FLAG-APRIL bound to TACI-Fc wasquantified using anti-FLAG M2 antibody conjugated with HRP (SigmaAldrich) used at 1:10000 dilution as described in Example 3. APRILimmunoreactive Hybridomas which also exhibited at least 10% inhibitionto either human APRIL or mouse APRIL were isolated, subcloned by limiteddilution, and reassessed for APRIL binding and blocking activity and IgGtiter by ELISA as described. Hybridomas with positive activity but lowIgG titers were further isotyped for determination of potentialIgM-producing clones. Positive hybridomas were selected for culturescale up, antibody purification and further characterization asdescribed in Example 2.

Example 2: Purification and Characterization of Anti-APRIL AntibodiesDerived from Mouse Hybridomas

Thirteen hybridoma clones from Example 1 were cultured at sequentiallyhigher scale from 96 well plates to 24 well plates and subsequently toT150 flasks (20 mL culture volume). Prior to purification, cells weretransferred out of HAT selective media into pre-defined, low Ig media.Supernatants were harvested 3-5 days after media transfer and clarifiedby centrifugation, followed by sterile filtration through a 0.22 μm PESmembranes (Corning). IgG titers were confirmed by Bioinferometry asdescribed. Supernatants were diluted 1:1 with 2× Protein G bindingbuffer (1M glycine, 2M NaCl, pH 9.0). Antibodies were purified byProtein G affinity chromatography using 1 mL Protein G HiTrap columns(GE Health Care) at a flow rate of 1 ml/min and as per themanufacturer's recommendations. IgG was eluted from the protein G columnby lowering pH using 0.1M glycine buffer, pH 2.8 followed by immediateneutralization using 2M TRIS, pH 8.5. Purified antibodies werereformulated by dialysis in 1×PBS, pH 7.4 followed by concentration byultrafiltration using an Ultra-30 AMICON 30 kD MWCO filtration unit.Final antibody concentration was determined spectrophotometrically byNanoDrop using a generalized extinction coefficient for murineantibodies (IgG1). Antibody purity and integrity was confirmed bySDS-PAGE under both reducing and non-reducing conditions. Antibodyisotype was determined using the Rapid ELISA Mouse mAb isotyping kit(Pierce/Thermofisher Scientific) in conjunction with preliminarysequence analysis (see Example 3). All purified antibodies weredetermined to be predominantly a distribution of IgG1 and G2a; lightchains were all determined to be of kappa class. A relatively smallersubset of APRIL immunoreactive antibodies derived from mice B-002/B-003(e.g., 02-009, 02-016, 046, FIGS. 1A-1B) were determined to be IgMs andnot carried forward for purification.

Purified antibodies were further characterized for APRIL binding, APRILspecies cross reactivity (human APRIL vs. mouse APRIL), and receptorblocking activity using TACI-Fc. For binding, an APRIL-based indirectELISA was used to determine by first approximation the relative affinityof purified anti-APRIL antibodies to either human APRIL or mouse APRIL.ELISA method was as generally described above. In brief, HA-GCN4 hAPRIL(amino acid residues 105-250) and HA-GCN4 mAPRIL (amino acid residues96-241) were coated at a density of 50 ng/well. Blocking and wash stepswere completed as described. Binding of anti-APRIL antibodies to APRILwas quantified using an 8 point dilution of test antibody that spannedover a four log scale. Antibody binding to APRIL was detected using arabbit anti-mouse IgG (H+L)-HRP conjugate (Jackson ImmunoResearchLaboratories). Antibody binding data was analyzed by non-linearregression analysis using a 3 parameter fit to determine max binding andapparent EC₅₀ values. The results are shown in FIG. 3. Human specific,anti-APRIL monoclonal antibodies h01A (described, e.g., in Guadagnoli,M. et al. Blood 117, 6856-6865 (2011)), herein described as mAb 1313,and A019C11 (described, e.g., in Jagessar, S. et al. J NeuroimmunePharmacol 7:557-570 (2012)), herein referred to as mAb 0201, were usedas positive controls for binding to human APRIL and for comparativepurposes. Mouse specific antibody Apry-1-1 (Adipogen) was likewise usedfor quantification of antibody binding to mouse APRIL.

Receptor blocking activity of anti-APRIL antibodies was likewisemeasured by ELISA using recombinant TACI or BCMA (extracellulardomain(s) expressed and purified as Fc fusion proteins in a bindingcompetition-based experiment. For this experiment, recombinant TACI-Fcor BCMA-Fc were produced in HEK 293 cells following transienttransfection of these cells using the Fc expression vector pc-tPA-Fc. Inbrief, this vector was constructed from parental mammalian expressionvector pcDNA3.1 (Life Technologies) using standard molecular cloningtechniques. Vector was designed to include a 5′ Kozak translationinitiation consensus sequence followed by an N-terminal tPA signalsequence for processing and optimized secretion of recombinant proteininto the media as a soluble protein. The c-termini of the extracellularAPRIL binding domains of human TACI or human BCMA were fused in frame tothe Fc portion of human IgG1 beginning at position E98 in CH1. DNAsequences were synthesized following codon optimization for mammalianexpression and initially cloned into pcDNA3.1 typically as a Bam H1-Xbacassette. Receptor variants were cloned into resultant vector asAsc1-Bbs1 or Asc1-Not 1 DNA fragments depending on design and cloningstrategy. TACI-Fc comprises human TACI sequences 29-110 that includesboth CRD1 and CRD2 domains and generally corresponds to the TACI-Fcbased receptor decoy atacicept. This sequence is herein described asHuTACI-Fc-001 (or more commonly as TACI-Fc unless otherwise noted). Avariant of TACI, likewise expressed as an Fc fusion protein onlyincludes CRD2. TACI may include the C-terminal region (or so-called“stalk”) from amino acids 110 to approximately 166 that immediatelyprecede the transmembrane domain. BCMA-Fc comprises the extracellularcytokine binding domain (amino acid residues 1-54) and herein describedas HuBCMA-Fc-001 (or more commonly as BCMA-Fc unless otherwise noted).

Recombinant TACI-Fc or BCMA-Fc was coated on 96 well plates in 0.1 Mcarbonate-bicarbonate buffer (pH 9.6), overnight at 4° C. Plates werewashed three times with 1×PBST (PBS+0.025% Tween 20) followed byblocking with 1% BSA in 1×PBS, 37° C. for 1 hour. All subsequent washsteps were carried out with 1×PBST. To assess antibody blocking, either15 ng/mL or 50 ng/mL HA-GCN4-huAPRIL was preincubated with varyingantibody concentrations ranging from 0.03-30 μg/mL in binding buffercomprised of 1% BSA and 0.025% Tween-20 in 1×PBS. Preincubation wascarried out at 30° C. for 1 hour with mixing. Antibody-APRIL premix with50 ng/mL APRIL or 15 ng/mL APRIL was then added to TACI-Fc coated orBCMA-Fc coated plates, respectively, and incubated for an additionalhour at 30° C. HA-tagged APRIL binding to either receptor was quantifiedusing a goat polyclonal anti-HA tag-HRP antibody (Abcam) added at a1:10000 dilution followed by colorimetric development using 100 μl/wellof freshly prepared TMB substrate (KPL) carried out for up to 30 minutesat room temperature before quenching enzymatic reaction by the additionof 1N sulfuric acid. ELISA signal was quantified by absorbance at 450nm. The results are shown in FIGS. 2A-2B and FIG. 3. ELISA data wasanalyzed by non-linear regression. IC₅₀ values were calculated based ona 4 parameter fit of antibody titration curves. Where appropriate, %inhibition is calculated based on normalization of data to no antibodycontrol (0% inhibition) vs. background (no APRIL), set as 100%inhibition. Anti-human mAb 1313 and mAb 0201 were used as positivecontrols and for comparative purposes. Non-blocking antibodies Aprly-1or Aprly-5 (Enzo Biosciences) were used as negative controls. Mousespecific, blocking antibody aprily-1-1 (Adipogen) was generally used asa positive control in experiments using mouse APRIL (HA-GCN4-mAPRIL).

The functional activity of anti-APRIL antibodies was also evaluatedusing a cell-based receptor signaling transduction assay. In this assay,binding of APRIL to either TACI or BCMA results in receptor activationleading, in turn, to downstream activation of NF-κB, a transcriptionfactor that ultimately mediates programmed changes in B cell geneexpression and phenotype. The use of established NF-κB reporter celllines for this purpose has been described in the literature. The use ofheterologous (non-lymphoid) cell lines lacking TACI or BCMA expressionbut wherein TACI or BCMA can be introduced exogenously throughtransfection allows for controlled, receptor defined analysis of APRILsignaling and inhibition of this signal by anti-APRIL antibodies. Forthis purpose, the commercial 293TN-derived NF-κB reporter cell lineNF-κB/293/GFP-Luc™ (System Biosciences) was chosen. These cells arestably transfected with the genes for both GFP and firefly luciferaseplaced in tandem under the transcriptional control of a minimal CMVpromoter (mCMV) and multiple copies of the NF-κB recognition element.

NF-κB/293/GFP-Luc™ cells were maintained and grown in 293TN Cell growthmedium (DMEM base medium supplemented with GlutaMAX and FBS) as permanufacturer's instruction. cDNA Expression plasmids pcMV6-XL4/TACI andpcMV6-XL4/BCMA (Origene) were used for transfections. These plasmidsencode full-length human TACI (TNFRSF13B, accession number NM_012452) orBCMA (TNFRSF17, accession number NM_001192) 293TN reporter cells weretransfected at a density of approximately 6×10⁵ cells/mL (>90%viability) using PEI-MAX as follows: For pcMV6-XL4/TACI, 10.4 ng/mL (˜1ng/well); for pcMV6-XL4/BCMA 83 ng/mL cell culture (˜8 ng/well). Totalplasmid concentration was held constant at 1.67 μg/mL culture volume(167 ng/well) using empty vector pcMV6-XL4 as needed to maintainconstant plasmid amounts for each transfection. Transfections werescaled appropriately based on number of plates needed. 100 μl oftransfection mix was transferred to each well. Plates were transferredto 37° C. incubator with 5% CO₂ for 20-24 hours.

On day 2, recombinant APRIL (HA-GCN4-APRIL) was preincubated withserially diluted antibody in complete 293TN culture media prior toaddition to cells. In brief, for APRIL-mediated activation of TACIsignal transduction, 40 ng/mL APRIL (2× target concentration) was mixed1:1 with serially diluted antibody (likewise diluted in cell culturemedia) in a 96 well plate; for APRIL-mediated activation of BCMA signaltransduction, 200 ng/mL APRIL (2× target concentration) was likewisemixed 1:1. Antibody-APRIL mix was incubated for 1 hour at 37° C. withshaking. 40 μl of preincubation was added to transfected cell culturefollowing removal of spent cell culture media. Cells were incubated at37° C. as above for an additional 20-24 hours. NF-κB-driven luciferaseactivity was subsequently quantified using ONE-Glo™ Luciferase kit(Promega) generally in accordance with manufacturer protocol, but withminor modifications. Relative fluorescent units (RLUs) were measured inOpaque white 96-well plates using a luminometer plate reader. Theresults are shown in FIG. 4. Data was normalized to no Ab control aftercorrecting for assay signal background (no APRIL). IC₅₀ values werederived from a non-linear regression analysis of antibody titrationcurves fit to a four fit parameter. Antibodies 1313 and 0201 typicallywere used as positive controls. In the case of using recombinant mouseAPRIL, apry1-1, was used as a positive control. Non-neutralizingantibodies anti human APRIL antibodies Aprily-1 or Aprily-5 weretypically used as negative controls.

Example 3: Determination and Molecular Cloning of Anti-APRILImmunoglobulin Sequences

VH and VL gene sequences of mouse antibodies derived from hybridomascreening were initially determined by reverse transcriptase PCR of Bcell RNA using a pool of pre-defined set of mouse Ig sequence-specificprimers of varying degeneracy. 5′ Primer design for VH sequencing wasbased on a comprehensive analysis of the mouse immunoglobulin databasewith corresponding alignment to variable leader sequences. From thisanalysis, VH leader sequences were clustered (or binned based onsequence relatedness and representation of germline “families”); aunique set of primers, each predicted to anneal more specifically tothese binned VH sequence families were designed and used as a cocktailin the RT-PCR reaction. 3′ primers were designed to anneal in theconstant region of the heavy chain. This primer set was naturally lesscomplex and corresponded to unique sequences in CH1 that define the fourknown mouse IgG constant regions (IgG1, IgG2a, IgG2b and IgG3). IgMrelated VH sequences were amplified as above but with substitution of anIgM isotype 3′ primer. Similarly, a so-called “pooled primer” RT-PCRapproach was used to amplify the corresponding VL sequences from mousehybridoma RNA. A systematic query of all known mouse VL leader sequenceswas likewise performed. As kappa and lambda light chains share neitherthe constant region nor variable region sequences, separate primer sets(kappa vs. lambda specific) were designed. 3′ primers were designedbased on isotype specific light chain constant region sequence (kappavs. lambda) in a manner analogous to the one described above for heavychain sequences. RT-PCR amplification of hybridoma gene sequences from Bcell RNA was completed using otherwise established methods. In brief,RNA was extracted from 0.5-2×10⁶ cells using the RNeasy kit (LifeTechnologies) as per manufacturer's instructions. Cell lysis wasfacilitated using Qiashredder or related method for initial nucleic acidextraction. Purified RNA was quantified by UV absorbance. cDNA synthesisand subsequent PCR amplification (using Platinum Taq polymerase andprimer mixes described above) were completed in tandem using SuperscriptIII One Step RT-PCR kit (Life Technologies). PCR amplicons were purifiedusing Qiaquick PCR clean up kit (Life Technologies) and quantified by UVabsorbance at 260 and 280 nm using a Nanodrop spectrophotometer. PCRproducts were also analyzed by agarose gel electrophoresis to confirmpredicted size and gel purified as needed. VH and VL gene sequences weredetermined by directly sequencing of PCR products using nested primers.Ambiguous sequence data was followed by re-amplification of cell RNA byRT PCR as described above but with modification to protocol and using asubset of smaller pooled primer sets; if necessary PCR products werecloned by TA cloning into an intermediate vector) and transformed intochemically competent TOP10 (Life Technologies) or DH5a (New EnglandBiolabs) as per the manufacturers protocols. DNA sequence data wasanalyzed using publically available databases (e.g., InternationalImmunogenetics Information system (IMGT), VBase, or NCBI Ig-Blast) toevaluate germline usage, identify CDR sequences and assign putativeisotype when possible. In general, this sequencing strategy led to theidentification of unique VH sequences for each hybridoma of interest;several clones resulted in the identification of multiple light chains.

Productive VH and VL Ig sequences were amplified by PCR and clonedseparately into mammalian Ig expression vectors o-pcMG2 and o-pcMK2,respectively, for recombinant production in HEK293 cells as paired mouseIgG2 (HC) and kappa (LC) isotyped antibodies. Gene-specific primers weredesigned based on VH and VL sequences identified as described above.Primer design included 18-23 overlapping nucleotides complementary tothe corresponding framework regions of the variable gene sequences inaddition to vector complementary sequences designed to enablerecombination based cloning by modified Gibson assembly fused in frameto variable region sequences through DNA ligation as described below.Primer design was assisted through the use of NEB Builder (New EnglandBiolabs) or Primer3 software. Additional Primer design included theincorporation of restriction endonuclease recognition sequences onrespective 5′ ends for subcloning as needed. In the case of ambiguousvariable sequences, primer design incorporated the use of modestlydegenerate nucleotide sequences (at 1-2 positions) or surrogate (“bestguess”) codons guided by the knowledge of the predicted germlineframework identified in the original VH and VL sequence analysis.

For molecular cloning by RT PCR, RNA was extracted from hybridomasgenerally as described. cDNA first strand was synthesized usingSuperscript III First Strand Synthesis Supermix (Life Technologies) asper the manufacturer's protocol. 2.5 μl of cDNA template DNA wasamplified by PCR using Q5 high fidelity DNA polymerase (New EnglandBioLabs). Amplification included a total of 35 cycles by “touch-up” PCR″using initially a three step amplification for 10 cycles followed by 25cycles involving 2 step amplification (annealing and extension both at72° C.). PCR amplicons were evaluated by agarose gel electrophoresis toconfirm purity, correct size, and approximate amounts. Gel purificationof PCR products was carried when necessary using Qiaquick gelpurification kit (Qiagen). HC and LC Ig expression vectors werelinearized and prepared for cloning by restriction endonuclease doubledigestion. 5′ ends of digested vectors were subsequentlydephosphorylated with shrimp alkaline phosphatase followed by heatinactivation of enzymes. PCR products were ligated into 50 ng linearizedvector (gel purified) using NEB Builder (New England Biolabs) at a 2:1mole ratio of insert:vector. 2 μl of ligation reaction was transformedinto chemically competent E. coli (DH5α, New England Biolabs) and platedon LB with antibiotic. Recombinant clones were selected by colony DNAsequencing followed by plasmid purification of positive clones at 200 mLE. coli scale using low endotoxin Purelink Maxiprep kits (LifeTechnologies) as per the manufacturer's protocols.

For recombinant antibody production, approximately 225 μg each ofpurified Ig expression vectors (HC and LC) were used to transientlytransfect HEK 293F cells. About 2×10⁶ cells/mL cells were transfectedusing PEI-Max-based transfection reagent and cultured in Freestyle 293cell media for a total of 5-7 days. Antibody titer was quantified bybioinferometry using Protein A-immobilized biosensors (Pall Biosensors).

Recombinant antibodies were purified from culture supernatant followingclarification by low speed centrifugation and sterile filtration through0.22 μm PES membranes followed by addition of a protease inhibitorcocktail (Cocktail III, Thermofisher) to mitigate against proteolysis.Antibodies were purified by Protein A affinity chromatography using a 1mL Protein A Hitrap column (GE Healthcare) with low pH elution asdescribed followed by neutralization by TRIS, pH 8.5. Antibodies werereformulated and concentrated in 1×PBS, pH 7.4 by tandem dialysis andultrafiltration using Amicon-Ultra 30 centrifugation concentrating units

Example 4: In Vitro Binding and Receptor Blocking Activities ofAnti-APRIL Antibodies

Recombinant anti-APRIL antibodies were characterized with respect toboth APRIL binding and receptor blocking activities using bothELISA-based and cell-signaling methods as described. As shown in FIGS.5-6, first-pass antibody binding to human APRIL by indirect ELISAindicated several antibodies with low and subnanomolar bindingaffinities to the cytokine target based on EC₅₀ values extrapolated fromnonlinear regression analyses of antibody titration curves. Antibodies2218, 2419, and 2621 in particular bound human APRIL with apparenttarget binding affinities of less than 0.2 nM; antibodies 3530 and 2922bound human APRIL with apparent target binding affinities between 0.2 nMand 1 nM. 3125 bound human APRIL with an apparently lower affinity (>1nM). Similar analysis of monoclonal antibody binding to mouse APRILhomologue indicated only mAb 3530 having appreciable cross-speciesbinding to target (data not shown). Functional analysis of antibodyblocking activity was evaluated by competition ELISA using receptor-Fcas the APRIL capture ligand in a 96 well based format as described. Thisanalysis included the use of both biologically relevant APRILTNFR-related receptors (human TACI and human BCMA) for purposes ofevaluating any selectivity with respect to the antibody-mediatedantagonism of APRIL-receptor interactions. As shown in FIG. 9, antibodyIC₅₀ values were calculated from a non-linear analysis of antibodytitration curves. Anti-human blocking antibodies 1313 and 0201 were usedas positive controls and for comparative purposes. Non-neutralizingantibody Aprily-5 (Enzo Biosciences) was used as a negative control.Based on this in vitro data, all of the recombinant antibodiesdemonstrated at least partial blocking of human APRIL to human TACI-Fc.As shown in FIG. 7, monoclonal antibodies 2218, 2419, 2621, 3327, and3530 blocked APRIL-TACI binding with corresponding IC₅₀ values in thelow or sub-nanomolar range. MAbs 3125 and 2922 would appear to blockwith somewhat lower potency, with IC₅₀ values greater than 10 nM. Asshown in FIG. 8, a similar evaluation of receptor blocking using BCMA-Fcindicates antibodies 2218, 2419, and 3327 are likewise able to blockBCMA binding with low or subnanomolar potency. MAb 3530 would appear tobe relatively selective with respect to blocking APRIL binding toTACI-Fc in comparison to BCMA-Fc; as such this antibody may be viewed asbeing “TACI selective.” MAb 2621 did not appear to block APRIL bindingto BCMA-Fc as evaluated in this assay; as such, mAb 2621 may be viewedas being a potentially “TACI-specific” antibody.

Functional (receptor antagonism) activity of anti-APRIL antibodies wasfurther evaluated using an orthogonal, cell-based NF-κB transcriptionalreporter assay to assess inhibition of APRIL-mediated receptor signalactivation. This assay involved the heterologous expression offull-length (transmembrane) TACI or BCMA by transient plasmidtransfection in and engineered HEK293 cell line possessing a stablytransfected NF-kB-transcriptionally activated luciferase reporter gene.Assay was generally carried out as described using recombinant Hu APRILas the exogenous source of receptor activating cytokine. Data wasnormalized to the minus antibody control after subtraction of signalbackground (no APRIL or Ab). The data are summarized in FIGS. 11A-11B.Based on these data, the potent receptor blocking activities ofmonoclonal antibodies 2218 and 2419 were further confirmed in anantibody-dose dependent manner. These activities included blocking ofboth BCMA and TACI receptors. Monoclonal antibodies 2922 and 3125qualitatively exhibited lesser activity, consistent with theirrelatively lower activities in the Receptor-Fc blocking ELISA (i.e., incomparison to mAbs 2218 and 2419). Apparent discrepancies between thesetwo assays may be attributed to differential receptor expression levels,protein turnover, or other biological factors not present in the lesscomplex ELISA based binding assays. Nevertheless, these data, takencollectively, demonstrate clear functional activity of the recombinantanti-APRIL antibodies with respect to antagonism of APRIL activitydescribed herein.

Additional experimental data include, for example, the following.Binding of exemplary anti-APRIL antibodies to human APRIL is shown inFIG. 16. Relative binding affinities of exemplary anti-APRIL antibodiesare shown in FIG. 17. Antibody inhibition of APRIL-mediated receptorsignaling is shown in FIGS. 18A-18B. Antibody inhibition of APRILbinding to TNFSF receptors TACI and BCMA is shown in FIGS. 19A-19B.Antibody inhibition of APRIL binding to both human TACI-Fc and humanBCMA-Fc is summarized in the table in FIG. 20.

Example 5: Species Cross-Reactivity of Anti-APRIL Antibodies

In addition to demonstrating the functional activity of severalanti-APRIL antibodies, the cross-reactivity of these antibodies withrespect to binding and blocking both mouse and human APRIL was alsoevaluated. This characterization employed the same set of in vitroassays as described but with the inclusion of analogously HA-taggedmouse APRIL (R&D Systems). For illustrative purposes, a subset of datafrom the receptor-Fc based blocking ELISA (both TACI-Fc and BCMA-Fc) isincluded. In this analysis, mAb 3530 was compared to antibodies 1313(human specific anti-APRIL blocking antibody), Apry-1-1 (mouse specificanti-APRIL blocking antibody) and non-neutralizing antibody Aprly-5(negative control). Antibody-titered receptor blocking activity data aresummarized in FIGS. 10A-10B for blocking APRIL binding to human TACI-Fcand human BCMA-Fc, respectively. Consistent with other data, mAb 3530would appear to be a “TACI-selective” antibody based on its relativeneutralization profile (TACI vs. BCMA). Moreover, this antibody was ableto apparently block both mouse and APRIL binding to TACI-Fc withcomparable potency (apparent IC₅₀ values). To our knowledge, this thefirst example of a species cross reactive anti-APRIL antibody with bothimplications with respect to epitope specificity as well as use inpreclinical development of this antibody using disease relevant(syngeneic) rodent models.

APRIL species cross blocking activities of anti-APRIL antibodies arealso shown in FIGS. 21A-21B.

Example 6: Functional Activity of Anti-APRIL Antibody for Reduction ofSerum IgA In Vivo

In addition to its role in promotion of tumor growth, the cytokine APRILplays several critical roles in the regulation of adaptive and mucosalimmunity vis-à-vis the modulation of B and T cell function. Thisimmunological activity includes induction of IgA production in B cellsthrough receptor-mediated induction of Ig class switching, B cellproliferation, and survival of IgA+ related plasma cells. This centralrole of APRIL in IgA production leads to its potential as a therapeutictarget for diseases involving the dysregulated production of IgA and/orformation of IgA-containing immune complexes. Such diseases wouldinclude but not limited to IgA nephropathy, IgA-related vasculitis(e.g., Henoch-Schodein purpura), SLE, IgA-related monoclonalgammopathies, alcoholic liver disease, etc. The biological potency ofanti-APRIL therapeutic antibody can therefore be evaluated in vivo baseddirectly on a reduction of serum IgA levels following the administrationof such an antibody in a laboratory rodent model. Toward this end, themouse-APRIL specific, blocking antibody Apry-1-1 (Adipogen) used asdescribed herein as a control for assessing anti-APRIL antibody activityin vitro was also used as a test article. Age-matched male B6C3F1 mice(6-10 weeks old) were dosed with 20 mg/kg antibody two times a week viaIP injection. 12 for 8 weeks. Saline for injection was used as thenegative (vehicle) control. Serum Isotype specific immunoglobulin levels(IgG, IgM, and IgA) were monitored individually by ELISA approximatelyevery 12 days. Body weights were monitored 3× weekly, hematology andserum chemistries, and general health of the animals was monitored on aregular basis. Blood was drawn prior to dosing (day 0, pre-bleeds).Survival bleeds occurred at the end of 2 weeks (end of phase I) at 4weeks, and 6 weeks. Terminal bleeds occurred at the end of 8 weeks. Theresults are shown in FIGS. 12A-12B.

In this study, chronic administration of a functional anti-APRILantibody with in vitro validated blocking activity led to a reduction inserum IgA levels below 50%. Reduction was observed by day 24 and wassustained over the course of antibody treatment. Treatment with themouse anti-APRIL antibody had no statistically differential effects ontotal Ig serum levels relative to the control; hematology and bloodchemistry likewise were not affected.

Example 7: Epitope Mapping

Human APRIL site-directed variants were used for epitope mapping. Asshown in FIG. 22, APRIL is depicted as a trimer (cyan, green, andmagenta). Typical epitope containing CRD2 high affinity receptor bindingsite is depicted in dark blue. Positions of amino acid changes are notedwith wildtype amino acid preceding number and mutation following (e.g.,R233G represents mutation of arginine at position 233 to glycine).

Epitope mapping of exemplary antibodies 4035, 2419, and 3833 wasperformed. Antibody binding to human and mouse variants was assessed byELISA. Comparison is made to reference antibody 1313. FLAG-tagged APRILwas captured from cell culture media using anti-FLAG antibody. Theresults are shown in FIGS. 23A-23B, 24A-24B, and 25A-25B. Differentiatedepitope mapping of exemplary anti-APRIL antibodies was performed by sitedirected mutagenesis. Primary characterization of human APRIL bindingsite was carried out by site-directed mutagenesis of select amino acidpositions within APRIL followed by evaluation of antibody binding tothese variants by ELISA. Exemplary data for three anti-APRIL antibodies4035 (solid circles), 2419 (solid squares), and 1313 (open triangles)are shown in FIG. 26 for illustrative purposes.

Differential binding profiles of exemplary anti-APRIL antibodies areshown in Table 6. Exemplary amino acid residues that bind to theanti-APRIL antibody molecules described herein are listed. One or moreof these residues form at least part of a binding region on APRIL.Exemplary residues within the binding region predicted to have an impacton binding (e.g., based on the site directed mutagenesis studiesdescribed herein) are noted by an “X”. Exemplary residues predicted tohave lesser or no impact on binding (e.g., based on the site directedmutagenesis studies described herein) are noted by an “N” forcomparative purposes.

TABLE 6 Differential Binding Profiles of Exemplary Anti-APRIL Antibodies(Table discloses SEQ ID NOS: 338-341, respectively, in order ofappearance) AA 1313 No 4035 No 3833 No 2419 No position AA Impact impactImpact impact Impact impact Impact impact 129 Asp 130 Asp 131 Ser 132Asp X 170 Leu 174 Val N X X 175 Thr 176 Phe X X N X 177 Thr 178 Met 179Gly 180 Gln 181 Val X N N X 190 Gln X X N X 192 Thr 195 Arg X X 196 Cys197 Ile 200 Met 201 Pro 202 Ser 203 His 205 Asp 206 Arg N X X 208 Tyr XX X N 226 Ser N 228 Ile N N X 230 Pro 231 Arg 232 Ala 233 Arg 237 Asn XN N N 241 His

Example 8: Humanization of Mouse Derived Anti-APRIL Antibodies

Select anti-APRIL antibodies were derived from mouse immunization asdescribed herein. The variable regions of select antibodies, namely2419, 4035, and 4540 were subsequently humanized for purposes ofpotential therapeutic use and mitigation of immunogenicity. In brief,humanization was performed by identifying human germlines proximal tothe mouse variable heavy (VH) and variable light (VL). Once identified,the complementarity determining regions (CDRs) from mAb2419 VH and VLwere grafted on the human VH and VL germline templates respectivelyusing structure-guided design. Additional mutations (including backmutations to the parental residue in the mouse mAb) were selectivelyintroduced based on visual inspection of the structural model. Thehumanized antibody constructs were recombinantly produced in HEK293cells following transient transfection of separate vectors for heavy andlight chain expression. Recombinant antibodies were purified by ProteinA affinity chromatography using standard methods. Humanized antibodieswere subsequently tested for binding to APRIL, functional receptorblocking (TACI-APRIL and BCMA-APRIL interactions) and thermal stabilityusing a differential scanning fluorescence protein unfolding assay.Relative activity and stability profiles were compared to parental,mouse antibodies upon which humanization was based.

Example 9: In Vitro Binding and Receptor Blocking Activities ofHumanized Anti-APRIL Antibodies

Relative binding of exemplary anti-APRIL antibodies was measured byindirect ELISA. The binding of humanized variants of mouse antibodies4035 and 2419 to human APRIL is shown in FIG. 27A-27B, respectively. Thebinding of a humanized variant of human-mouse cross-reactive antibody4540-063 to both human APRIL and mouse APRIL is shown in FIGS. 28A-28B,respectively. Comparison of humanized anti-APRIL antibodies to parental(non-humanized) mouse antibodies is made for comparative purposes.Extrapolated EC₅₀ values are summarized in FIGS. 29A-29B. The exemplaryantibody molecules bind to APRIL with picomolar affinity.

The apparent binding affinities of antibodies 2419-1406 and 4035-062 totrimeric human APRIL were also measured by ELISA. APRIL trimer wasstabilized by the N-terminal fusion of APRIL with an isoleucine zipper(GCN4) oligomerization domain Binding of APRIL to human TACI-Fc is shownfor comparative purposes. The ELISA binding results are shown in FIG.29C. Picomolar EC₅₀ values derived from the binding curves depicted inFIG. 29C are summarized in FIG. 29D. The antibody showed picomolar (pM)binding to trimeric human APRIL as measured by ELISA. Higher affinitybinding of 2419-1406 and 4035-062 to APRIL relative to APRIL binding toits own receptor (TACI-Fc) was observed.

The inhibition of APRIL binding to TNFSF receptors TACI and BCMA byhumanized IgG2K variants of parental, murine derived antibody 2419 wasmeasured. Assay is based on receptor blocking ELISA using recombinanthuman APRIL (R&D Systems) and either human TACI-Fc (FIG. 30A) or BCMA-Fc(FIG. 30B). Parental, chimeric 2419 (mouse VH-VL grafted on to humanIgG1κ constant regions) is included for comparative purposes as ischimeric anti-human APRIL antibody 4035. Inhibition was analyzed bynon-linear regression using a four parameter curve fit followingnormalization to 100% activity (no antibody control). IC₅₀ values aresummarized in FIG. 33.

The inhibition of APRIL binding to TNFSF receptors TACI (FIG. 31A) andBCMA (FIG. 31B) by additional humanized variants of 2419 (IgG2K)2419-0205 and 2419-1406 and humanized variant (4035-062) of parentalantibody 4035 was measured. Humanized 4035-062 is of the IgG1κ subtype.Chimeric, non-humanized versions of mouse derived antibodies 4035 and2419, and 1313 are included for comparative purposes. mAb1313 is acontrol anti-APRIL antibody. TACI-Fc and BCMA-Fc were used. IC₅₀ valuesare summarized in FIG. 33.

The inhibition of APRIL binding to TNFSF receptors TACI (FIG. 32A) andBCMA (FIG. 32B) by humanized variants of mouse/human APRILcross-neutralizing antibody 4540 was measured. Humanized antibody 4540is of the IgG1κ subtype. Parental 4540 (non-humanized chimera) andhumanized 4035-062 (FIGS. 30A-30B) are included for comparativepurposes. Inhibition was analyzed by non-linear regression using a fourparameter curve fit as described for FIGS. 29A-29B and FIGS. 30A-30B.IC₅₀ values are also summarized in FIG. 33. Sub-nanomolar blocking ofAPRIL-receptor binding was observed for most of the tested antibodies.

These results indicate that humanization and reformatting (e.g., asIgG2) generally, if not always, leads to comparable retention ofreceptor blocking activities.

The antibody inhibition of APRIL-mediated receptor signaling wasevaluated. Inhibition of APRIL-receptor mediated NFκB intracellularsignaling was evaluated using the HEK 293 NFκB reporter cell linefollowing transient transfection of either full-length human TNF familyreceptors TACI or BCMA cDNA expression vectors. Data are normalized tono antibody control (100%). The inhibition of TACI- and BCMA-mediatedNFκB signaling is shown in FIGS. 34A-34B, respectively.

FIG. 35 depicts the approximate IC₅₀ values of antibody inhibition ofAPRIL-mediated receptor signaling. Data are extrapolated from FIGS.34A-34B based on a non-linear regression analysis using a variableslope, three parameter fit of antibody concentration vs. response.Negative antibody control (no APRIL binding) demonstrated no activity inthis assay (data not shown). These results indicate potent inhibition ofAPRIL-mediated NFκB downstream signaling pathway (with low or sub-nMIC₅₀) by exemplary anti-APRIL antibody molecule. Blocking occurs withboth TACI and BCMA receptors.

Example 10: Evaluation of Anti-APRIL Antibody Binding Specificity toAPRIL

Selected anti-APRIL antibodies were evaluated for potentialcross-reactivity with other members of the TNFa superfamily (TNFSF)family of cytokines, including: human TNFα (TNFSF2; Adipogen), humanCD40 (TNFSF4, Adipogen), human FasL (TNFSF6, Adipogen), human TRAIL(TNFSF10, Adipogen), human RANKL (TNFSF11; Adipogen), human Tweak(TNFSF12; Abcam), human and mouse BAFF (TNFSF13B, AB Biosciences andAdipogen, respectively), and human LIGHT (TNFSF14, Adipogen). Thesecytokines share variable degree of sequence as well as higher orderstructural homologies. Among them, BAFF appears to be the most closelyrelated to APRIL, with 29% identity and 53% amino acid sequencesimilarity.

Binding was evaluated by an indirect ELISA protocol using similarmethods described for evaluation of APRIL binding; cytokines wereimmobilized to ELISA plate at 50 ng per well and then exposed to asolution of each of the test antibodies at a fixed concentration of 10μg/ml Anti-human or anti-mouse Ig-HRP polyclonal antibody conjugates(Jackson Laboratories) were used for detection of antibody binding. Theresults presented in FIG. 36 indicated eleven of the twelve antibodiestested in this assay to specifically bind APRIL with no measurablecross-reactivity with the other TNFSF members substantially above assaybackground. Antibody 4338 demonstrated detectable binding to both thehuman and mouse versions of BAFF and was used as an assay control.

mAbs 2419-1406 and 4035-062 demonstrate minimal or no extraneous proteincross-reactivity in extensive array of over 4500 human membrane proteins(RETROGENIX™). An example of protein expression array design is shown inFIG. 37A. Confirmatory/secondary screen was performed on 12 proteins(FIGS. 37B-37C). Binding to Fc receptors was observed for both 2419-1406and 4035-062 as predicted. Weaker binding to FcγR1 was observed forantibody 2419-1406 consistent with it having an IGg2 isotype. Negligiblebinding to PDGFR was also detected for 2419-1406. Binding to any othermembrane targets except those described was not observed Antibody4035-062

Example 11: Identification of Target Epitope for Maximal Anti-APRILAntibody Potency

The epitope of an exemplary anti-APRIL antibody molecule, mAb 2419, wasmapped using a combination of empirical and computational tools anddata. These methods and resultant data included 1) low resolutioncrystallography of mAb 2419 Fab in complex with human APRIL (amino acids115-250) in tandem with 2) structural modeling (FIG. 38A), and 3) APRILsaturation mutagenesis at select positions within the surface of APRILcarried out in combination with APRIL surface display in yeast (FIG.38B). As shown in both FIGS. 38A-38B, the antibody molecule targets anon-linear, quaternary epitope spanning two different monomers of APRILwithin a larger trimeric complex. The epitope of 2419 also substantiallyoverlaps with a region of APRIL corresponding to the high affinityreceptor binding site (CRD2 site) critical for both TACI and BCMAreceptor blocking (FIG. 38B). A secondary receptor binding site (CRD1site) also overlaps with the 2419 epitope with implications for blockingTACI-APRIL interactions. Based on this analysis, positions within APRILthat define the epitope of 2419 include V133, V181, E185, Q187, G188,R189, Q190, E191, T192, R195, H218, L219, H220, S226, 1228, P230(located in monomer A); V121, I123, Q139, P140, A141, L142, N237, 5239,P240, and H241 (located in monomer B).

A more focused analysis of this epitope by mutagenesis of selectsurface-accessible positions of APRIL point to a subset of positionswithin the larger epitope of 2419 (structurally depicted in FIG. 38A)that appear to particularly critical for antibody binding. Theseso-called “hotspot residues”, i.e., those residues that are critical tothe interaction between APRIL and mAb 2419, are empirically defined)using a combination of the methods described above) as those positionswhere mutation from the wildtype sequence to nearly any other aminoresidue resulted in a substantial loss of binding of 2419 to APRIL.Examples of such positions include V181, Q190, T192, and 1228 on onemonomer, and A141 and H241 on an adjacent monomer.

TABLE 8 Exemplary Human APRIL Amino Acid Residues that Bind to mAb 2419(amino acid numbering based on SEQ ID NO: 85) Position Human MonomerHotspot V133 A V181 A Y E185 A Q187 A G188 A R189 A Q190 A Y E191 A T192A Y R195 A H218 A L219 A H220 A S226 A I228 A Y P230 A V121 B I123 BQ139 B P140 B A141 B Y L142 B N237 B S239 B P240 B H241 B Y

In summary, the epitope overlaps predicted regions for maximal receptorblocking, and targets a non-linear, quaternary epitope spanning twodifferent monomers of APRIL, implications for neutralizing biologicallymost active form of APRIL (trimer).

Example 12: Pharmaceutical Properties of Anti-APRIL Antibodies

Thermal stability of exemplary anti-APRIL molecules, 2419-1406 and4035-062, were measured using Sypro-Orange® fluorescence scanning assay(FIG. 39A). The thermal melting temperatures (Tm values) for both2419-1406 and 4035-062 are listed in FIG. 39B. mAb 2419-1406 and mAb4035-062 exhibit high thermal stability.

The tg32 mouse model was used as a surrogate for predicting the PK ofantibody pharmacokinetics (PK) in humans. PK of control antibody (IgG1)with pre-established PK of approximately 25 days (in humans) was alsoevaluated in this study for comparative purposes. As shown in FIGS.40A-40B, favorable PK profile of an exemplary anti-APRIL antibodymolecule, 2419-1406 and 4035-062, in humanized FcRn transgenic mousestrain tg32 was observed.

Example 13: Species Cross-Reactive Anti-APRIL Antibodies EffectivelyReduce Serum IgA Levels in Mice

Mouse mAb 4540 is a cross-species reactive (mouse and human) anti-APRILwith receptor neutralizing activity. mAb 4540 targets an overlappingAPRIL epitope to mAb 2419-1406. mAb4540 was used as a surrogate toevaluate the effect of anti-APRIL mAb treatment on a reduction of serumIgA levels in C57/BL6 mice. 11 week old mice were sub-chronically dosed(1× weekly by i.p injection) with 20 mg/kg of mAb 4540, mAb 3833, orisotype control antibody for seven weeks. Basal serum levels of totalIgA were quantified by ELISA. As shown in FIG. 41, treatment of mAb 4540or mAb 3833 reduced serum IgA levels in C57/BL6 mice.

INCORPORATION BY REFERENCE

All publications, patents, and Accession numbers mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

What is claimed is:
 1. A nucleic acid molecule encoding three heavychain complementarity determining regions (HCDR1, HCDR2, and HCDR3) andthree light chain complementarity determining regions (LCDR1, LCDR2, andLCDR3) of an anti-APRIL antibody molecule, wherein the HCDR1 comprisesthe amino acid sequence of SEQ ID NO: 11; the HCDR2 comprises the aminoacid sequence of SEQ ID NO: 12, and the HCDR3 comprises the amino acidsequence of SEQ ID NO: 13; and the LCDR1 comprises the amino acidsequence of SEQ ID NO: 280; the LCDR2 comprises the amino acid sequenceof SEQ ID NO: 285, and the LCDR3 comprising the amino acid sequence ofSEQ ID NO: 16; or wherein the HCDR1 comprising the amino acid sequenceof SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ IDNO: 282, and the HCDR3 comprises the amino acid sequence of SEQ ID NO:13; and the VL comprises an LCDR1 comprising the amino acid sequence ofSEQ ID NO: 280; the LCDR2 comprises the amino acid sequence of SEQ IDNO: 285, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:16.
 2. The nucleic acid molecule of claim 1, wherein: (a) the VHcomprises the amino acid sequence of SEQ ID NO: 296, 283, 288, 289, 291,292, 294, or 317, or an amino acid sequence that is at least 85%, 90%,95%, or 99% identical thereto; (b) the VL comprises the amino acidsequence of SEQ ID NO: 286, or an amino acid sequence that is at least85%, 90%, 95%, or 99% identical thereto; or (c) both (a) and (b).
 3. Thenucleic acid molecule of claim 1, wherein: (a) the VH comprises theamino acid sequence of SEQ ID NO: 296; (b) the VL comprises the aminoacid sequence of SEQ ID NO: 286; or (c) both (a) and (b).
 4. The nucleicacid molecule of claim 1, wherein the anti-APRIL antibody molecule is asynthetic antibody molecule, an isolated antibody molecule, or ahumanized antibody molecule.
 5. The nucleic acid molecule of claim 1,wherein the anti-APRIL antibody molecule comprises: (a) a heavy chainconstant region of IgG1, IgG2, IgG3, or IgG4; (b) a light chain constantregion of kappa or lambda light chain; or (c) both (a) and (b).
 6. Thenucleic acid molecule of claim 1, wherein the anti-APRIL antibodymolecule comprises a heavy chain constant region of IgG2.
 7. The nucleicacid molecule of claim 1, wherein the anti-APRIL antibody moleculecomprises a light chain constant region of kappa or lambda light chain.8. The nucleic acid molecule of claim 1, wherein the anti-APRIL antibodymolecule comprises an Fc region.
 9. The nucleic acid molecule of claim1, wherein the anti-APRIL antibody molecule comprises two VHs and twoVLs, or comprises a Fab, F(ab′)2, Fv, or single chain Fv (scFv)fragment.
 10. A nucleic acid molecule encoding a heavy chain variableregion (VH), a light chain variable region (VL), or both, of ananti-APRIL antibody molecule, wherein the VH comprises three heavy chaincomplementarity determining regions (HCDR1, HCDR2, and HCDR3) and the VLcomprises three light chain complementarity determining regions (LCDR1,LCDR2, and LCDR3), wherein the VH comprises an HCDR1 comprising theamino acid sequence of SEQ ID NO: 11; an HCDR2 comprising the amino acidsequence of SEQ ID NO: 12, and an HCDR3 comprising the amino acidsequence of SEQ ID NO: 13; and the VL comprises an LCDR1 comprising theamino acid sequence of SEQ ID NO: 280; an LCDR2 comprising the aminoacid sequence of SEQ ID NO: 285, and an LCDR3 comprising the amino acidsequence of SEQ ID NO: 16; or wherein the VH comprises an HCDR1comprising the amino acid sequence of SEQ ID NO: 17; an HCDR2 comprisingthe amino acid sequence of SEQ ID NO: 282, and an HCDR3 comprising theamino acid sequence of SEQ ID NO: 13; and the VL comprises an LCDR1comprising the amino acid sequence of SEQ ID NO: 280; an LCDR2comprising the amino acid sequence of SEQ ID NO: 285, and an LCDR3comprising the amino acid sequence of SEQ ID NO:
 16. 11. The nucleicacid molecule of claim 10, wherein: (a) the VH comprises the amino acidsequence of SEQ ID NO: 296, 283, 288, 289, 291, 292, 294, or 317, or anamino acid sequence that is at least 85%, 90%, 95%, or 99% identicalthereto; (b) the VL comprises the amino acid sequence of SEQ ID NO: 286,or an amino acid sequence that is at least 85%, 90%, 95%, or 99%identical thereto; or (c) both (a) and (b).
 12. The nucleic acidmolecule of claim 10, wherein: (a) the VH comprises the amino acidsequence of SEQ ID NO: 296; (b) the VL comprises the amino acid sequenceof SEQ ID NO: 286; or (c) both (a) and (b).
 13. The nucleic acidmolecule of claim 10, wherein the anti-APRIL antibody molecule is asynthetic antibody molecule, an isolated antibody molecule, or ahumanized antibody molecule.
 14. The nucleic acid molecule of claim 10,wherein the anti-APRIL antibody molecule comprises: (a) a heavy chainconstant region of IgG1, IgG2, IgG3, or IgG4; (b) a light chain constantregion of kappa or lambda light chain; or (c) both (a) and (b).
 15. Thenucleic acid molecule of claim 10, wherein the anti-APRIL antibodymolecule comprises a heavy chain constant region of IgG2.
 16. Thenucleic acid molecule of claim 10, wherein the anti-APRIL antibodymolecule comprises a light chain constant region of kappa or lambdalight chain.
 17. The nucleic acid molecule of claim 10, wherein theanti-APRIL antibody molecule comprises an Fc region.
 18. The nucleicacid molecule of claim 10, wherein the anti-APRIL antibody moleculecomprises two VHs and two VLs, or comprises a Fab, F(ab′)2, Fv, orsingle chain Fv (scFv) fragment.
 19. A vector comprising the nucleicacid molecule of claim
 10. 20. A cell comprising the nucleic acidmolecule of claim
 10. 21. A method of producing an anti-APRIL antibodymolecule, the method comprising culturing a cell of claim 20 underconditions that allow production of an antibody molecule, therebyproducing the antibody molecule.
 22. A nucleic acid molecule comprising:(i) a first nucleotide sequence encoding a heavy chain variable region(VH) comprising the amino acid sequence of any of SEQ ID NOs: 296, 283,288, 289, 291, 292, 294, or 317; (ii) a second nucleotide sequenceencoding a light chain variable region (VL) comprising the amino acidsequence of SEQ ID NO: 286; or (iii) both (i) and (ii).
 23. A vectorcomprising the nucleic acid molecule of claim
 22. 24. A cell comprisingthe nucleic acid molecule of claim
 22. 25. A method of producing ananti-APRIL antibody molecule, the method comprising culturing a cell ofclaim 24 under conditions that allow production of an antibody molecule,thereby producing the antibody molecule.
 26. A nucleic acid moleculecomprising: (i) a first nucleotide sequence of any of SEQ ID NOs: 73,304, 307, 308, 309, 310, 311, 313, or 319, or a nucleotide sequence thatis at least about 85%, 90%, 95%, 99% or more identical thereto, ordiffers by no more than 3, 6, 15, 30, or 45 nucleotides therefrom; (ii)a second nucleotide sequence of SEQ ID NO: 306, or a nucleotide sequencethat is at least about 85%, 90%, 95%, 99% or more identical thereto, ordiffers by no more than 3, 6, 15, 30, or 45 nucleotides therefrom; or(iii) both (i) and (ii).
 27. The nucleic acid molecule of claim 26,comprising: (i) a first nucleotide sequence of any of SEQ ID NOs: 73,304, 307, 308, 309, 310, 311, 313, or 319; (ii) a second nucleotidesequence of SEQ ID NO: 306; or (iii) both (i) and (ii).
 28. A vectorcomprising the nucleic acid molecule of claim
 26. 29. A cell comprisingthe nucleic acid molecule of claim
 26. 30. A method of producing ananti-APRIL antibody molecule, the method comprising culturing a cell ofclaim 29 under conditions that allow production of an antibody molecule,thereby producing the antibody molecule.